Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Introduction
The studies on TGF-β started as early as the 1980s and have developed rapidly ever since. Although TGF-β was first found to be secreted by transformed cells,1 it is widely produced by non-neoplastic tissues such as salivary glands, muscles, kidneys, liver, heart, brain, and embryos as well.2,3,4 In fact, platelets have been identified as one of the most abundant sources of TGF-β among all normal tissues.5 The ubiquitous expression of TGF-β in health strongly indicates its critical and multiple roles in physiological conditions.
Accumulating evidence has suggested that TGF-β functions diversely among different cell types in a context-dependent manner. Generally, cell survival, metabolism, growth, proliferation, differentiation, adhesion, migration, and death are all under the regulation of TGF-β. Proper TGF-β signaling is critical to the normal functioning and homeostasis of healthy bodies while aberrant TGF-β signaling can lead to diseases of various categories. For this reason, numerous targeted therapies that can remedy dysregulated TGF-β activity have been developed with some demonstrating encouraging safety and efficacy in clinical trials.
In this review, we focus on the mechanism, physiology, pathology, as well as therapeutics of TGF-β signaling, aiming to provide historical, current, and future perspectives on relevant topics.
History of research on TGF-β signaling
TGF-β was first reported in 1978 when De Larco and Todaro discovered the ‘sarcoma growth factors’ which were produced by transformed murine fibroblasts and were able to transform normal fibroblasts to anchorage-independent growth.1 In 1981, Roberts et al. successfully isolated and purified TGF-β from non-neoplastic murine tissues,3 while at about the same time, Moses et al. independently accomplished the purification and characterization of the cytokine as well.6 Both groups also noticed that this relatively acid- and heat-stable polypeptide required disulfide bonds for activity and was sensitive to disulfide-reducing agent dithiothreitol. In 1983, studies by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels indicated that the 25,000-dalton TGF-β molecule in humans was actually composed of two 12,500-dalton subunits cross-linked by disulfide bonds.7,8 Two years later, the amino-acid sequence of human TGF-β1, the first known TGF-β isoform, was revealed by Derynck et al. through direct protein sequencing and complementary deoxyribonucleic acid (DNA) cloning.2 The sequencing established that the 112-amino-acid-long TGF-β1 monomer is initially synthesized as the C-terminal segment of a 390-amino-acid-long precursor polypeptide.2 By the time of 1988, researchers had realized that TGF-β generally remained non-covalently associated with the N-terminal segment of its precursor when it was secreted.9,10 TGF-β cannot bind to its receptors with its receptor-binding site being masked in this inactive form, however, certain treatments such as acidification could convert latent TGF-β complex into active TGF-β ligand.11 In addition, the other two TGF-β isoforms in mammals, TGF-β2 and TGF-β3, were respectively identified in 198712 and 1988.13,14 Although the three TGF-β isoforms are encoded by three different genes, their mature ligands show strong conservation of amino acid sequences.
The effects of TGF-β signaling in cell proliferation,15,16 cell differentiation,17,18 embryonic development,19 wound healing,20 immune regulation,21,22 tissue fibrosis,23,24 and tumor development25,26 have been studied shortly after the discovery of the cytokine. Meanwhile, the receptors in TGF-β signaling known as TGF-β receptor I (TβRI) and TβRII were also identified and characterized in the 1980s.27,28,29 But it was not until the discovery of signaling mediators small (Sma) in Caenorhabditis elegans and mothers against decapentaplegic (Mad) in Drosophila melanogaster that the homologous small mothers against decapentaplegic (SMAD) proteins were identified as the canonical signal transducers of TGF-β signaling in humans in 1996.30,31,32 Since then, the development of TGF-β research has been largely accelerated. In recent times, as studies on TGF-β signaling in both health and disease going deeper and further, a lot of TGF-β-targeting therapies have been developed and assessed for the treatment of various diseases,33,34,35,36,37,38,39 revealing a promising future for the studies in this area (Fig. 1).
Biosynthesis and activation of TGF-β
During the biosynthesis of TGF-β, the precursor undergoes post-translational processing to become a latent complex which is the secretory form of TGF-β. The latent TGF-β complex still requires further activation to eventually become a mature cytokine before it can trigger signal transduction in cells (Fig. 2).
TGF-β biosynthesis and latency
Each TGF-β monomer is initially synthesized as a precursor polypeptide composed of a mature cytokine as its C-terminal segment, a signal peptide at the N-terminus, and a latency-associated peptide (LAP) in between.2 The signal peptide leads the precursor into the endoplasmic reticulum lumen and promptly gets removed. The remainder of the precursor then dimerizes through three disulfide bonds and transits into the Golgi where it gets cleaved between the mature cytokine and LAP by protease furin.40 However, the cytokine segment is still unable to bind its receptors after the cleavage, for it remains associated with LAP in a non-covalent way that masks its receptor-binding site and forms a small latent complex (SLC).41 In most cases, LAP is linked to latent TGF-β-binding protein (LTBP) through a disulfide bond, making the SLC into a large latent complex (LLC) when secreted.42 LTBP can further bind to fibrillin to target the LLC into the extracellular matrix (ECM) for storage.43 Alternatively, LAP can also form disulfide linkage with leucine-rich repeat-containing protein 32 (LRRC32) or LRRC33 to tether SLC to the cell surface. Unlike LTBP which is widely expressed by many cell types, LRRC32, also known as glycoprotein-A repetitions predominant protein (GARP), is specifically detected in regulatory T cells (Tregs), platelets, and endothelium,44 whereas high expression of LRRC33 is found in macrophages, dendritic cells (DCs), and B cells.45
TGF-β activation
The bioactivity of TGF-β is based on ligand-receptor interaction which requires the exposure of its receptor-binding site. Thus, the activation of TGF-β represents the release of mature cytokine from the latent complex. Numerous factors have been identified as TGF-β activators as introduced below. Notably, integrin-dependent activation is so far the best described and likely the most important mechanism, while TGF-β activation mediated by acids, bases, reactive oxygen species (ROS), thrombospondin-1 (TSP-1), proteases, and other TGF-β activators is collectively known as integrin-independent activation.
TGF-β activation by integrins
Integrins are heterodimeric transmembrane receptors each consisting of an α-subunit and a β-subunit. TGF-β activation by integrins requires the binding of the integrins to an RGD sequence in the LAP of TGF-β1 and TGF-β3. Therefore, latent TGF-β2 without the RGD motif is excluded from integrin-dependent activation.46
Among all integrins, αVβ6 and αVβ8 integrins are the best studied TGF-β activators. The expression of αVβ6 integrin is nearly restricted to epithelial cells and is upregulated in response to morphogenesis, wounding, inflammation, and tumorigenesis.47 In contrast, αVβ8 integrin is widely expressed by epithelial cells,48 fibroblasts,49 macrophages,50 DCs,51 Tregs,52 and different kinds of tumor cells.53 The lack of αVβ6 and αVβ8 integrin activity reproduces the phenotypes of TGF-β1- and TGF-β3-null mice, indicating the central importance of integrin-dependent activation.54,55
Upon binding to the RGD motif in LAP, the mechanisms by which αVβ6 and αVβ8 integrins activate TGF-β are quite different. With latent TGF-β being tethered to ECM or cell membrane (through the binding of LAP to LTBP, GARP, or LRRC33 as mentioned before) and the cytoplasmic domain of integrin β6 subunit linking to the actin cytoskeleton, αVβ6 integrin can transmit contractile force which changes the conformation of LAP to release TGF-β ligand.56,57 However, the cytoplasmic domain of integrin β8 subunit does not link to the actin cytoskeleton. One effective mechanism for αVβ8 integrin-mediated TGF-β activation requires the proteolytic activity of membrane type 1-matrix metalloproteinase (MT1-MMP, also known as MMP14).48 Alternatively, membrane molecules such as GARP and LRRC33 which bind and present latent TGF-β on the surface of one cell can cooperate with the αVβ8 integrin expressed on a different cell to activate TGF-β in trans.45,58,59 A recent study reveals that upon binding to αVβ8 integrin, the flexible membrane-presented latent complex can expose the active domain of the TGF-β ligand to its receptors for binding and signaling without the need to release diffusible cytokine.60
TGF-β activation by acids and bases
It has long been noticed that acidification can unmask the activity of freshly secreted TGF-β.61 Sharply defined parameters for human TGF-β activation by acids and bases show that the transition from latency of all three isoforms occurred between pH 2.5 and 4, and between pH 10 and 12.62 Thus, extremely acidic environments such as the microenvironments in tumor tissues and the resorption lacunae of osteoclasts are possibly conducive to local TGF-β activation.63,64 A study on lung fibrosis even suggests that physiologic concentrations of lactic acid are sufficient enough to activate TGF-β in a pH-dependent manner.65
TGF-β activation by ROS
TGF-β1 is the only isoform that can be directly activated by ROS, for a unique methionine residue at the amino acid position 253 of its LAP is required for oxidation-triggered conformational change.66 However, ROS can induce other TGF-β activators such as TSP-167 and MMPs68 to activate all three isoforms in an indirect manner. ROS-mediated TGF-β activation prevails in tissues exposed to asbestos,69,70 ultraviolet,68 and ionizing radiation.71 High glucose intake can also induce ROS production and consequentially increase TGF-β activation to play roles in the development of fibrotic diseases and inflammatory diseases.72,73 Moreover, in T cells, ROS can be elevated during apoptosis or upon stimulation by T cell receptor (TCR) and cluster of differentiation 28 (CD28) to contribute to the immunosuppression mediated by activated TGF-β.74,75
TGF-β activation by TSP-1
TSP-1 is a multi-functional ECM protein not only abundant in platelet α-granules but also secreted by fibroblasts, endothelial cells, macrophages, T cells, and many other cell types.76 The KRFK sequence in TSP-1 can recognize the LSKL sequence in LAP to competitively disrupt its interaction with the receptor-binding site of the TGF-β ligand. Since the LSKL sequence in LAP is conserved among TGF-β isoforms, it is suggested that the direct binding of TSP-1 to latent complex is capable of activating all three TGF-β isoforms through this protease- and cell-independent mechanism.77 Interestingly, TSP-1 can also bind to the mature TGF-β ligand to form a complex that retains the biological activity of the cytokine.78 ROS,67 glucose,79 angiotensin II,80 hypoxia,81 wounding,82 inflammation,83 pathogens,84,85,86 and many other factors can all induce TSP-1 to function as a TGF-β activator in wound healing,67,82 cardiovascular diseases,81,86 renal diseases,79 fibrotic diseases,87,88 inflammatory diseases,83 infectious diseases,89 and tumors.90
TGF-β activation by proteases
Many proteases have been proved capable of directly activating TGF-β in vitro. However, the function of an individual protease seems redundant in vivo, as deficiency of a single species generally leads to no significant signs of impaired TGF-β activation.91 Among these proteases, MMPs such as MMP-2, MMP-9, and MMP-13 are conducive to the TGF-β activation in wound healing,92 cardiovascular diseases,93 renal diseases,94 fibrotic diseases,95 and tumors.96 Interestingly, although the activation by MMPs works for all three TGF-β isoforms, latent TGF-β2 and TGF-β3 appear much more sensitive to MMP-9 treatment than latent TGF-β1.96 Moreover, a serine protease known as plasmin plays an important role in the TGF-β activation mediated by macrophages97,98 and endothelial cells.99,100
Signal transduction of TGF-β
TGF-β signal is transmitted into the cells by TβRI (also known as activin receptor-like kinase 5, ALK5) and TβRII both of which are enzyme-linked receptors with dual specificity of serine/threonine kinase and tyrosine kinase. Studies have revealed that TGF-β1 and TGF-β3 bind TβRII prior to TβRI due to higher affinity, while TGF-β2 binds poorly to both receptors.12,101,102 TβRIII, also known as β-glycan, lacks the motifs to directly mediate TGF-β signal transduction. However, TβRIII is able to bind TGF-β especially TGF-β2 with high affinity and thus acts as a co-receptor that presents the ligand to the receptors and further enhances their binding.101,103,104,105,106,107 The ligand-receptor interaction subsequently activates the intracellular signaling of TGF-β through a canonical pathway and several non-canonical pathways.
Canonical TGF-β signaling
The canonical TGF-β signaling is mediated by transcription factors SMADs and thus is also known as the SMAD signaling. Notably, the canonical pathway is under the regulation of various factors that can control the intensity and manner of cellular responses at different levels (Fig. 3).
TGF-β-activated SMAD signaling
TGF-β ligand initially binds to TβRII monomer to promote its homodimerization or directly binds to pre-existing TβRII homodimer to recruit TβRI for assembly.108,109,110,111 This forms a heteromeric TGF-β-TβRI-TβRII complex in which low-affinity TβRI requires high-affinity TβRII to bind TGF-β ligand and constitutively active TβRII requires phosphorylating TβRI to transduce intracellular signal.112 The phosphorylation of TβRI occurs in its juxtamembrane GS domain at several serine and threonine residues, triggering conformational changes that transform the GS domain from a site that binds the signaling inhibitor known as immunophilin FK506-binding protein 1A (FKBP12) into a binding site for the signaling effectors known as receptor-activated SMADs (R-SMADs).113
R-SMADs, including SMAD2 and SMAD3, consist of a globular Mad homology 1 (MH1) domain at the N-terminus, a globular MH2 domain at the C-terminus, and a highly flexible long linker region in between. R-SMADs are retained in cytoplasm and presented to TβRI by the adaptor protein known as SMAD anchor for receptor activation (SARA).114 The R-SMAD MH2 domain then gets phosphorylated at two serine residues in the extreme C-terminal SXS motif by the TβRI kinase domain which is located immediately downstream of the TβRI GS domain.113 Activated R-SMADs undergo homo-oligomerization or hetero-oligomerization through their MH2 domains upon phosphorylation, and they can also oligomerize with SMAD4, the common-partner SMAD (co-SMAD) which lacks the SXS motif for phosphorylation by TβRI kinase. Notably, studies have suggested that SMAD heterotrimers containing two R-SMADs and one SMAD4 are likely more common and stable than other SMAD oligomers.115,116,117,118,119 Although different SMAD oligomers can vary in function, they all act to regulate the transcription of target genes by binding to DNA after translocating into the nucleus. The MH1 domains of SMAD4, SMAD3, and a specific SMAD2 splicing variant recognize the nucleic acid sequence GTCT or its reverse complement AGAC in double-stranded DNA which are known as the canonical SMAD-binding elements (SBEs).120 Other SBEs such as the 5GC SBEs including GGCGC and GGCCG have also been discovered, indicating a relatively loose DNA-binding specificity of the SMAD oligomers.121 However, the binding to a single SBE is so weak that SMAD oligomers generally require interacting with replications of SBE copies as well as other DNA-binding sequence-specific transcription factors to function.119,120,122 In fact, many SBE repeats are enriched at the binding sites for SMAD-interacting transcription factors, exactly increasing the binding accessibility, specificity, and affinity of SMAD oligomers associated with specific transcription factors.123,124,125 Despite a large number of SMAD-interacting transcription factors indicating a huge amount of potential gene targets for canonical TGF-β signaling, the dominant effects are generally determined by the master transcription factors in specific cell types and contexts which contribute to the complexity and variability of cellular responses to TGF-β.125
Regulation of SMAD signaling by inhibitory SMADs (I-SMADs)
TGF-β and many other factors can induce the expression of SMAD6 and SMAD7 which function to inhibit TGF-β signaling and thus are known as I-SMADs.126,127 Unlike R-SMADs, I-SMADs lack the N-terminal MH1 domain and the C-terminal SXS motif, however, they retain the C-terminal MH2 domain which can competitively bind to activated receptor TβRI to inhibit the phosphorylation of R-SMADs.128,129 Through some extra mechanisms, SMAD7 confers greater abilities in suppressing TGF-β signaling than SMAD6 does.130 For example, SMAD7 recruits E3 ubiquitin ligases such as SMAD ubiquitination regulatory factors (SMURFs) and neural precursor cell expressed, developmentally downregulated 4-like (NEDD4L) to TβRI, R-SMADs, and co-SMAD to mediate the proteasomal and lysosomal degradation of these TGF-β signaling components.131,132,133,134,135 SMAD7 can also trigger the dephosphorylation of TβRI by recruiting protein phosphatase 1 (PP1) to the receptor.136 Moreover, with its MH2 domain, SMAD7 can oligomerize with R-SMADs to compete with co-SMAD133 and can bind to specific DNA sequences to disrupt the formation of the transcriptional SMAD-DNA complex.137 Taken together, TGF-β signaling induces I-SMADs to form a negative feedback loop of itself.
Regulation of SMAD signaling by transcriptional cofactors
Transcriptional cofactors are actively recruited to the transcriptional SMAD complex to regulate its activity. Notably, many of these transcriptional cofactors have histone modification activity and thus enable TGF-β signaling to trigger epigenetic changes. Histone acetyltransferases (HATs) such as p300, cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein (CBP), p300/CBP-associated factor (PCAF), and general control non‐repressed protein 5 (GCN5) act as the transcriptional coactivators of SMADs by increasing the accessibility to DNA.138,139,140,141 The interaction between p300/CBP and doubly phosphorylated R-SMADs requires SMAD4 for stabilization and is critical for SMAD-mediated transcriptional activation. Other SMAD coactivators include melanocyte-specific gene 1 (MSG1),142 zinc finger E-box-binding homeobox 1 (ZEB1),143,144 and the histone methyltransferase (HMT) known as SET domain-containing protein 7 (SETD7).145 Contrary to HATs, histone deacetylases (HDACs) generally act as the transcriptional corepressors of SMADs by decreasing the accessibility to DNA. SMAD3 can directly recruit HDAC4 and HDAC5 to gene promoters to inhibit the function of transcription factors via histone deacetylation.146 SMADs can also associate with HDACs through interaction with other corepressors such as TGF-β-induced factor (TGIF),147 ecotropic viral integration site 1 (EVI1),148,149 Sloan-Kettering Institute proto-oncogene (SKI),150,151,152 as well as SKI-related novel gene N (SNO).153 Other transcriptional corepressors of SMADs include cellular-myelocytomatosis viral oncogene (MYC),154 SMAD nuclear-interacting protein 1 (SNIP1),155 ZEB2,143,156 and HMTs such as suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain bifurcated 1 (SETDB1) which can both trigger the methylation of histone 3 lysine 9 (H3K9) at gene promoters.157,158
Regulation of SMAD signaling by SMAD modifications
Post-translational modifications can also regulate the functions of SMADs. Apart from TβRI kinase which phosphorylates R-SMADs in their C-terminal SXS motif to mediate their activation, many other protein kinases such as mitogen-activated protein kinase kinase kinase 1 (MAPKKK1),159 p38 MAPK,160 c-Jun N-terminal kinase (JNK),161 extracellular signal-regulated kinase (ERK),162,163,164 rat sarcoma (RAS) homolog (Rho)-associated coiled-coil-containing protein kinase (ROCK),160 glycogen synthase kinase (GSK)-3β,165,166,167 calcium/calmodulin-dependent protein kinase II (CAMK2),168 protein kinase C (PKC),169 PKG,170 and several cyclin-dependent kinases (CDKs)167,171,172 can phosphorylate R-SMADs as well as co-SMAD at many different sites to enhance or attenuate SMAD activity. Meanwhile, the various phosphorylation of SMADs can be reversed by phosphatases. Several nuclear phosphatases known as the small C-terminal domain phosphatases (SCPs) can specifically dephosphorylate the linker region and MH1 domain of R-SMADs,173,174 whereas protein phosphatase, magnesium/manganese-dependent 1A (PPM1A),175 myotubularin-related protein 4 (MTMR4),176 and protein phosphatase 2A (PP2A)177 catalyze the dephosphorylation of the C-terminal SXS motif to terminate the signaling and promote the dissociation and cytoplasmic localization of SMADs.
Furthermore, SMADs can be ubiquitinated and deubiquitinated respectively by E3 ubiquitin ligases and deubiquitylating enzymes (DUBs). The E3 ubiquitin ligases that can mediate SMAD ubiquitination include SMURFs,135,178,179,180 NEDD4L,134,181 WW domain-containing proteins (WWPs),182,183,184 really interesting new gene (RING) finger protein 111 (RNF111),185 C-terminus of heat shock protein (HSP) 70-interacting protein (CHIP),186 itchy (ITCH) E3 ubiquitin ligase,187 and S-phase kinase-associated protein (SKP)-cullin-F-box (SCF) E3 ubiquitin ligase complex.188,189 The ubiquitination generally leads to the proteasomal degradation of SMADs, but in some cases, it also exerts non-degradative effects on SMAD activity.190 Notably, the degradative ubiquitination of R-SMADs by NEDD4L requires the phosphorylation of the R-SMAD linker by CDK8/9 and GSK-3 in sequence to create binding sites for the E3 ubiquitin ligase.171,181,191
Non-canonical TGF-β signaling
Apart from the SMAD-dependent pathway, TGF-β can also signal through SMAD-independent pathways to activate ERK signaling, Rho guanosine triphosphatase (GTPase) signaling, p38 MAPK signaling, JNK signaling, nuclear factor-κB (NF-κB) signaling, phosphatidylinositol 3-kinase (PI3K)/AKR mouse thymoma proto-oncogene (AKT) signaling, as well as Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. These non-canonical TGF-β signaling pathways are involved in an extensive range of cellular events, greatly expanding the participation of TGF-β signaling in health and disease (Fig. 4).
TGF-β-activated ERK signaling
As a dual-specificity kinase, TβRI can phosphorylate at its tyrosine residues to activate ERK signaling upon TGF-β stimulation.192 In this case, TβRI with tyrosine kinase activity initially phosphorylates the adapter protein known as sarcoma (SRC) homology and collagen A (SHCA) which subsequently forms a complex with growth factor receptor-bound protein 2 (GRB2) and son of sevenless homolog (SOS). The SHCA-GRB2-SOS complex then initiates a canonical MAPK signaling cascade which involves the sequential activation of RAS, the MAPKKK known as RAS-associated factor (RAF), the MAPKK known as MAPK/ERK kinase (MEK), and eventually, the ERK MAPK. Activated ERK is known to regulate various biological events including cell survival, proliferation, differentiation, adhesion, migration, as well as metabolism, and is implicated in a spectrum of diseases such as developmental disorders, chronic inflammation, neurodegeneration, obesity, and cancers.193,194
TGF-β-activated Rho GTPase signaling
Rho GTPases such as RHO, RAS-related C3 botulinum toxin substrate 1 (RAC1), and cell division cycle 42 (CDC42) play a central role in the organization and dynamics of the actin cytoskeleton. They are activated by guanine nucleotide exchange factors (GEFs) through the exchange of a bound GDP for GTP.195 TGF-β can trigger RHO activation in a rapid SMAD-independent manner or by inducing a GEF known as neuroepithelial cell transforming 1 (NET1) through SMAD and MEK/ERK pathways.196,197,198,199,200 RHO then activates its key effector ROCK1 which further mediates the phosphorylation of LIM domain kinase 2 (LIMK2). Activated LIMK2 subsequently phosphorylates cofilin to inhibit its function as a constitutive actin-depolymerizing factor, leading to the reorganization of the actin cytoskeleton in the end.201,202,203 Additionally, TGF-β-triggered RHO/ROCK1 signaling can contribute to ERK phosphorylation,204,205 and besides RHO, TGF-β can also activate the signaling of other Rho GTPases such as RAC1202 and CDC42.206 Besides the regulation of cell morphogenesis, adhesion, and movement, Rho GTPase signaling is also known to participate in transcriptional regulation, cell cycle progression, vesicular trafficking, and pathological processes such as fibrosis, inflammation, wound repair, and tumor development.207,208
TGF-β-activated p38, JNK, and NF-κB signaling
TGF-β can activate the signaling of another two MAPKs known as p38 and JNK through a receptor kinase-independent mechanism which is different from that of ERK signaling. TGF-β-activated TβR complex can recruit tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and TRAF6 to trigger their lysine 63 (K63)-linked polyubiquitination. With E3 ubiquitin ligase activity, polyubiquitinated TRAF then attaches the polyubiquitin chain on the MAPKKK known as TGF-β-activated kinase 1 (TAK1) which subsequently gets activated and phosphorylates several MAPKKs (MKKs).209,210,211 As a result, MKK3 and MKK6 specifically trigger the activation of p38 while MKK4 mediates the phosphorylation of both p38 and JNK. TGF-β-activated Rho GTPases such as RHOA, RAC1, and CDC42 can also contribute to p38 and JNK activation.204,212,213,214,215,216 Both the two MAPKs regulate a series of biological events to respond to all kinds of environmental and intracellular stresses, meanwhile, they engage actively in embryonic development, metabolic regulation, neuronal functions, immunological actions, as well as tumor development.217,218,219,220
Additionally, TGF-β-activated TRAF/TAK1 signaling, RHO/ROCK1 signaling, and PI3K/AKT signaling can also lead to the phosphorylation of NF-κB inhibitor (IκB) kinase (IKK).221,222,223,224 Activated IKK then triggers the phosphorylation of IκB which subsequently gets polyubiquitinated and degraded while releasing active NF-κB for nuclear translocation.221 NF-κB as a transcription factor can regulate hundreds of genes involved in cell survival, proliferation, metabolism, and immunity in particular.225,226,227
TGF-β-activated PI3K/AKT signaling
The TβR complex can activate the lipid kinase PI3K upon TGF-β stimulation, either via the kinase activity of TβRI or through the recruitment of TRAF6, which polyubiquitylates PI3K regulatory subunit p85α independent of the receptor kinase.228,229 Activated PI3K then phosphorylates phosphoinositide phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3) which further triggers the phosphorylation of AKT.228,230 Activated AKT targets plenty of substrates, including mechanistic target of rapamycin (MTOR),231,232 GSK-3β,233 and several forkhead box O (FOXO) transcription factors.234Among them, MTOR is the most common downstream effector of AKT, and ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) are the best-characterized downstream effectors of MTOR. In general, the consequences of PI3K/AKT signaling include diverse cellular responses such as survival, metabolism, growth, proliferation, and differentiation.235
TGF-β-activated JAK/STAT signaling
TGF-β is found to induce JAK1 and JAK2 activation respectively in hepatic stellate cells (HSCs) and fibroblasts. In these cases, activated JAK triggers the phosphorylation of STAT3 which functions to mediate the fibrogenic effects of TGF-β, including increased cell proliferation, myofibroblast (MF) differentiation, ECM production, α-smooth muscle actin (α-SMA) expression, and stress fiber formation.236,237,238 Like other signaling pathways, JAK/STAT signaling can also drive many physiological and pathological events, including development, metabolism, immunity, wounding, and cancers.239
TGF-β signaling in health
In physiological conditions, TGF-β signaling is greatly required by multiple biological processes and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis (Fig. 5).
Embryonic development
In situ hybridization and immunohistochemical staining reveal overlapping but distinct expression patterns of the three TGF-β isoforms at different developmental stages of murine embryos. TGF-β is expressed in nearly all kinds of embryonic tissues such as heart, vessels, lungs, kidneys, liver, gut, bones, teeth, cartilages, muscles, skin, thymus, thyroid, suprarenal glands, salivary glands, nervous system, and craniofacial tissues.19,240,241,242,243,244 In particular, mesenchymal and epithelial components undergoing organogenesis and morphogenesis which involve active cell differentiation and epithelial-mesenchymal interactions generally express high levels of TGF-β.19,240,241,242,243
TGF-β has a significant impact on cell differentiation. Studies on Xenopus embryos reveal that TGF-β can induce mesoderm formation which is a primary patterning event in early vertebrate development.245,246 TGF-β can further regulate the development of hemangioblasts from mesoderm as well as subsequent differentiation of hematopoietic stem and progenitor cells (HSPCs) to participate in hematopoiesis and vasculogenesis.240,247,248,249,250 Mesenchymal stem cells (MSCs) which are derived from the mesoderm as well also respond actively to TGF-β signaling during their differentiation into several connective tissue cell lineages such as osteocytes, chondrocytes, myocytes, and adipocytes.251,252 TGF-β inhibits osteogenic differentiation by inducing the nuclear translocation of β-catenin and repressing the transcriptional activity of core-binding factor subunit α-1 (CBFA1) in a SMAD3-dependent manner.252,253 TGF-β-induced SMAD signaling also inhibits myogenesis and adipogenesis by respectively repressing the transcriptional activity of myogenic differentiation (MYOD) family members254,255,256,257 and CCAAT/enhancer-binding proteins (C/EBPs).17,258,259 However, the differentiation of MSCs into smooth muscle cells (SMCs) is promoted by TGF-β through mechanisms involving the activation of SMAD signaling, RHO signaling, and NOTCH signaling.260 Moreover, TGF-β stimulates chondrogenesis by inducing mesenchymal cells to differentiate into chondrocytes and produce cartilage-specific proteoglycan and type II collagen.18,261,262 As for other cell types, TGF-β signaling also regulates the differentiation and development in epidermis,263 lungs,264,265 kidneys,266 pancreas,267,268 teeth,269 and nervous system.270,271,272,273,274,275,276
Especially for epithelial cells, TGF-β can induce a reversible de-differentiation process known as epithelial-mesenchymal transition (EMT) which is critical to embryonic development.277 During EMT, epithelial cells lose their cellular polarity, intercellular junctions, and epithelial markers such as E-cadherin, but turn to acquire mesenchymal or fibroblastic phenotype with increased cell migratory motility, ECM proteolytic activity, and expression of mesenchymal markers such as fibronectin.278 This process is generally mediated by transcription factors such as SNAIL, SLUG, ZEB, and TWIST, involving both SMAD-dependent and SMAD-independent pathways in the case of TGF-β signaling.198,200,219,230,231,232,279,280 The developmental functions of TGF-β-induced EMT have been well studied in embryonic palate formation during which the expression of TGF-β is significantly elevated.19,243 Among the three TGF-β isoforms expressed in developing murine palate,281,282 only TGF-β3 is indispensable to the fusion of palatal shelves which is a crucial step during palatogenesis.283 Mechanically, TGF-β3 induces the EMT of palatal midline epithelial seam (MES) cells, leading to the disintegration of the epithelium and subsequent confluence of the mesenchyme.279,280 Interestingly, endothelial cells can undergo a similar process known as endothelial-mesenchymal transition (EndMT) which is crucial for cardiovascular development. In humans, TGF-β2 is the most potent inducer of EndMT, while TGF-β1 and TGF-β3 at least partially rely on the induction of TGF-β2 to trigger this process.284 Consistently, although all three TGF-β isoforms are differentially expressed during murine cardiogenesis,19,240,242,243,285,286,287 only TGF-β2 is obligatory to the EndMT during the endocardial cushion development in the atrioventricular canal which is necessary to valvular formation.288,289,290,291 Moreover, TGF-β1 and TGF-β2 can trigger EndMT in the epicardium to contribute to coronary vessel formation.292,293 In fact, TGF-β signaling is essential to vasculogenesis in many developing tissues by promoting the proliferation and migration of endothelial cells.19,294
Furthermore, TGF-β can induce apoptosis of unnecessary cells during embryonic development to ensure proper histogenesis and organogenesis. During murine palatogenesis, the disintegration of MES not only relies on TGF-β3-induced EMT as introduced above but also requires TGF-β3-induced apoptosis of MES cells to complete palatal confluency.295 In murine limb buds, highly expressed TGF-β triggers massive cell death in the mesenchyme of interdigital spaces to induce the regression of interdigital webs and the formation of free digits.19,243,296 Endogenous TGF-β also mediates the apoptotic death of certain neuron types in chick embryos to contribute to nervous system development.297 Notably, TGF-β2 and TGF-β3 presenting in the central part of the developing chick retina are essentially required to trigger retinal cell apoptosis, which can create space for incoming axons of retinal ganglion cells to form optic nerve.298,299 In mice, however, TGF-β signaling also protects retinal neurons from excessive apoptosis to ensure proper development of eyes.300
Wound healing
Wound healing which happens after tissue injuries generally involves four orderly and overlapping stages known as hemostasis, inflammation, proliferation, and remodeling.301 Throughout the healing of cutaneous wounds, all TGF-β isoforms and TβR types are induced in a distinct spatial and temporal pattern.302,303 During hemostasis, platelets provide an immediate and abundant supply of TGF-β after wounding, contributing largely to subsequent healing stages by promoting the influx of inflammatory cells and fibroblasts into the wounds due to its chemotactic activity.302,304,305,306,307 Interestingly, many of the cell types recruited by TGF-β are also active in secreting TGF-β, leading to even higher TGF-β concentrations in the wounds. In ovine skin, all three TGF-β isoforms increase dramatically only one day after wounding, attributed to the expression by epithelial cells, endothelial cells, fibroblasts, and inflammatory cells such as neutrophils, macrophages, and lymphocytes.302 During the stage of proliferation and remodeling, TGF-β is implicated in wound re-epithelialization, tissue angiogenesis, and fibroblast activation.308,309 Upon cutaneous injury, TGF-β1 is initially expressed by all epidermal keratinocytes adjacent to the wounds but gradually gets excluded from the basal keratinocytes, corresponding to the transient block and subsequent burst of basal keratinocyte proliferation after wounding.310 TGF-β1 also contributes to the migration of epithelial sheets at the leading edges of cutaneous wounds through the regulation of integrins and the activation of PI3K.310,311,312 Other TGF-β isoforms such as TGF-β3 can have similar impacts on cell migration during cutaneous wound healing.313 As for angiogenesis, TGF-β regulates the proliferation and migration of endothelial cells in vitro and shows potent angiogenic activity when overexpressed or directly applied in vivo.307,314,315,316,317,318,319,320,321 A possible mechanism of TGF-β-induced angiogenesis involves the induction of vascular endothelial growth factor (VEGF) in epithelial cells and fibroblasts.322,323 Moreover, TGF-β can stimulate fibroblasts to proliferate and produce bioactive factors such as collagen, fibronectin, MMPs, tissue inhibitor of MMPs (TIMPs), and plasminogen activator inhibitor 1 (PAI-1) which contribute to the deposition and remodeling of wound ECM.304,306,307,315,317,321,324,325,326,327,328,329,330,331,332,333,334 It can also promote fibroblast-mediated wound contraction through MF differentiation and RHO activation.335,336,337
Apart from the skin, TGF-β also functions in the repair and regeneration of many other tissues. During rat liver regeneration, all TGF-β isoforms are induced in non-parenchymal cells rather than hepatocytes, which however, exhibit upregulation of all TβR types to enhance the responsiveness to TGF-β, which may help to prevent uncontrolled cell proliferation.338,339,340,341,342 Similarly, the marked increase in TGF-β and TβR expression following acute pancreatitis suggests the role of TGF-β signaling in pancreatic repair.343,344,345 Upon vascular injury, TGF-β mobilizes MSCs to peripheral blood and further recruits them to the injured sites for vascular repair.346 As for cardiac repair after myocardial injury, TGF-β triggers the EndMT of epicardial cells, which then migrate into the injured myocardium to generate various cardiac cell types.347 TGF-β also plays a role in cartilage repair by stimulating proteoglycan synthesis in chondrocytes.348,349 Moreover, after injury in the nervous system, neurons, astrocytes, microglia, as well as recruited macrophages all upregulate the expression of TGF-β which may contribute to the healing process of the nervous tissues.350,351
Tissue homeostasis
Tissue homeostasis is maintained by the balance between cell proliferation and cell death in which TGF-β acts as a key regulator.
Cell proliferation is generally driven by CDKs through a series of events collectively known as the cell cycle. For most cells, TGF-β inhibits their proliferation, or in other words, triggers their cytostasis by inducing cell cycle arrest in the gap 1 (G1) phase. In epithelial cells and glial cells, TGF-β suppresses the activity of CDKs by activating the transcription of CDK inhibitors (CKIs) such as p15 and p21 to induce cytostasis.352,353,354,355 The transcriptional activation of CKIs in response to TGF-β is likely mediated by SMADs in cooperation with transcription factor FOXO355,356 or specificity protein 1 (SP1).357,358 Notably, the SMAD-FOXO complex additionally requires transcription factor C/EBPβ for the induction of p15 but not of p21.356 In epithelial cells, TGF-β-mediated upregulation of p15 also prevents the non-inhibitory binding of CKI p27 to CDK4. As a result, p15 and p27 turn to bind their own targets which are respectively CDK4 and CDK2 to exert their inhibitory effects.359,360 Interestingly, in murine B cells, TGF-β increases the expression of p27 instead of p21 to trigger cytostasis,361 while in human hematopoietic cells, p57 is likely the only TGF-β-induced CKI for cell cycle arrest.362 Besides CKIs, TGF-β can also target other proliferative factors such as MYC, inhibitors of DNA binding (IDs), and CDC25A to inhibit cell proliferation as mostly shown in epithelial cells. TGF-β induces the transcriptional repression of MYC through a complex containing SMADs, transcription factors E2F4/5 and C/EBPβ, as well as transcriptional corepressor p107.356,363,364 It also inhibits ID1 expression through SMADs which mediate the induction and recruitment of transcriptional repressor activating transcription factor 3 (ATF3) to target ID1 promoter.365 As for ID2 which can be induced by MYC at the transcriptional level, its suppression by TGF-β is attributed to the downregulation of MYC or the upregulation of antagonistic MYC repressors known as MYC-associated factor X (MAX) dimerization proteins (MADs).366,367 By these means, TGF-β is able to relieve the transcriptional repression on CKIs exerted by MYC and IDs to facilitate the induction of cytostasis.368,369,370,371 Furthermore, TGF-β can downregulate the activity of the CDK-activating phosphatase CDC25A through several mechanisms such as the transcriptional repression by E2F4-p130-HDAC1 complex,372 the inhibitory phosphorylation by RHOA/ROCK1 signaling,373 as well as the SMAD3-dependent degradative ubiquitination by E3 ubiquitin ligase complex SCF.374 Notably, TGF-β can also stimulate the proliferation of certain cell types, including SMCs, fibroblasts, and chondrocytes, likely due to the induction of autocrine growth factors such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF).324,325,375
As for cell death, TGF-β can trigger apoptosis which is one of the most common forms of cell death in a wide range of cell types including lymphocytes, hepatocytes, podocytes, glial cells, hematopoietic cells, and epithelial cells. Such effect is generally attributed to SMAD-dependent regulation of B-cell lymphoma-2 (BCL-2) family members. More specifically, TGF-β can upregulate pro-apoptotic BCL-2 family members such as BCL-2-associated X protein (BAX) and BCL-2-interacting mediator of cell death (BIM),376,377,378,379 meanwhile, it can also downregulate anti-apoptotic BCL-2 family members such as BCL-2 and BCL-extra-large (BCL-XL).378,380,381 Apart from BCL-2 family members, many other effectors and pathways are also involved in TGF-β-induced cell apoptosis. A septin-like protein known as apoptosis-related protein in the TGF-β signaling pathway (ARTS) undergoes mitochondrial-to-nuclear translocation to promote cell apoptosis in response to TGF-β.382 Death domain-associated protein (DAXX) interacts with TβRII as an intermediary to convey pro-apoptotic TGF-β signal to downstream machinery.383 In B cells and hepatocytes, TGF-β triggers the transient activation of TAK1/IKK/NF-κB pathway, sequentially leading to the transcriptional activation of IκB-α, the post-repression of NF-κB, the upregulation of JNK signaling, the increase of activator protein 1 (AP-1) complex activity, and finally, the apoptotic death of cells.384,385,386 In hepatocytes, TGF-β also promotes the expression of growth arrest and DNA damage-inducible β (GADD45β), which functions as a positive mediator of cell apoptosis by acting upstream of p38 MAPK.387 As for podocytes, TGF-β can activate both pro-apoptotic p38 signaling and anti-apoptotic PI3K/AKT signaling to regulate their survival and death.379,388 In fact, AKT, especially when phosphorylated, can bind to unphosphorylated SMAD3 to inhibit its activity and thus protect several cell types from SMAD-dependent apoptosis. In contrast, TGF-β can prevent the AKT-SMAD3 interaction by triggering SMAD3 phosphorylation to facilitate the cell death program.389,390 Moreover, in hematopoietic cells, SMAD-dependent TGF-β signaling induces the expression of a central regulator of phospholipid metabolism known as SRC homology 2 (SH2) domain-containing inositol 5’-phosphatase (SHIP) to inhibit AKT phosphorylation as well as cell survival.391 Furthermore, TGF-β triggers the apoptosis of oligodendrocytes and epithelial cells by inducing transcription factors TGF-β-inducible early genes (TIEGs) to downregulate BCL-XL expression.392,393,394 Notably, TGF-β is also found to promote cell survival in certain cases.300,395,396,397,398 Related mechanisms involve the AKT-dependent inhibition of FOXO3 as in epithelial cells,399 the suppression of AKT and the induction of BCL-2 as in pre-B lymphocytes,400 the early induction and phosphorylation of c-Jun and consequential attenuation of JNK as in lung carcinoma cells,401 the downregulation of CD95L and p53 as well as the upregulation of NF-κB, BCL-XL, and p21 as in HSCs.402
Immune homeostasis
Generally, TGF-β functions to suppress the activity of multiple immunocompetent cells while inducing the phenotypes of several immune immunosuppressive cells. For this reason, it is regarded as one of the most potent immunosuppressive cytokines which are of vital importance to the maintenance of immune homeostasis and self-immune tolerance.403
Cytotoxic T lymphocytes (CTLs), T helper type 1 (Th1), and Th2 cells
TGF-β prevents naïve T cells from differentiating into classical effecter T cells through numerous mechanisms. For CD8+ T cells which can develop into CTLs upon activation, TGF-β inhibits their functions by suppressing the expression of cytolytic factors such as perforin, granzyme A, granzyme B, Fas ligand, and interferon (IFN)-γ. Mechanically, the encoding genes of granzyme B and IFN-γ are directly recognized by SMADs and transcription factor ATF1 which both bind to the gene promoter regions to mediate transcriptional repression in response to TGF-β signaling.404 The suppression of IFN-γ release is also correlated to the reduction of transcription factor T-box expressed in T cells (T-BET)405 while the decrease in Fas ligand expression is partially attributed to the downregulation of MYC.406 In CD4+ T cells, TGF-β inhibits the phosphorylation of T-cell kinase (ITK) to decrease the influx of calcium ion and subsequent activation of nuclear factor of activated T cells (NFATC) which are both critical events for Th1 and Th2 cell differentiation.407 TGF-β also suppresses the expression of transcription factors T-BET and GATA-3 in CD4+ T cells which act as master transcriptional activators during Th1 and Th2 cell development respectively.408,409,410
Tregs, Th9, and Th17 cells
TGF-β induces the expression of transcription factor forkhead box P3 (FOXP3) in an interleukin (IL)-2-dependent manner in CD4+ CD25− naïve T cells to convert them into CD4+ CD25+ Tregs which can express TGF-β and inhibit other T cell proliferation with potent immunosuppressive activity.411,412,413,414 Similarly, TGF-β can induce the generation of Tregs from CD8+ T cells through the expression of FOXP3.415,416 Interestingly, IL-4 inhibits the induction of FOXP3 by TGF-β in naïve CD4+ T cells, instead, both cytokines cooperate to drive the differentiation of another Th cell subset known as Th9 cells by inducing the expression of transcription factor purine-rich box-1 (PU.1).417,418,419 Unlike the immunosuppressive Tregs, these IL-9- and IL-10-secreting cells can potently promote tissue inflammation.417,418,419,420 In addition, inflammatory cytokines such as IL-1β, IL-6, IL-21, and IL-23 also suppress TGF-β-induced FOXP3 in naïve CD4+ T cells, meanwhile, they elevate the activity of a TGF-β-induced transcription factor known as retinoic acid receptor-related orphan receptor γt (RORγt) to contribute to the generation of Th17 cells. This pro-inflammatory Th cell subset characterized by IL-17 expression plays important roles in anti-microbial defense and autoimmunity.421,422
B cells
As critical effectors of humoral immune responses, B cells mainly function by secreting antibodies which are also known as immunoglobulins (Igs). TGF-β decreases B cell Ig secretion by inhibiting the synthesis and the switch from the membrane form to the secreted form of Ig messenger ribonucleic acids (mRNAs).423 More specifically, TGF-β selectively inhibits the expression of Ig λ light chains while inducing less pronounced reductions in Ig κ light chains,423,424 moreover, it suppresses the production of isotypes IgM and IgG but enhances the class switching to isotype IgA.423,425,426 Notably, TGF-β-induced IgA with poor specificity is considered insufficient to mediate immune responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).427,428 Furthermore, TGF-β can convert B cells into regulatory B cells (Bregs) which produce numerous factors such as TGF-β, IL-10, IL-35, Fas-L, and programmed death-ligand 1 (PD-L1) to mediate immunosuppression.429,430,431,432
Natural killer (NK) cells
NK cells are cytotoxic lymphocytes of the innate immunity. TGF-β suppresses NK cell development by downregulating transcription factor E4 promoter-binding protein 4 (E4BP4) in a SMAD3-dependent manner.433 The SMAD3 also decreases NK cell IFN-γ secretion through the inhibition of E4BP4 and T-BET.433,434 Moreover, TGF-β downregulates the surface expression of NK triggering receptors such as NKP30 and NK group 2 member D (NKG2D) which are responsible for the recognition and killing of target cells.435,436 It also negatively regulates the expression of cytolytic factors such as granzyme A, granzyme B, and perforin through SMAD signaling to further impair NK cytotoxicity.434,436
DCs, macrophages, and neutrophils
DCs, macrophages, and neutrophils can function as antigen-presenting cells (APCs), which are the keys to the activation of adaptive immune responses. TGF-β can impair antigen presentation through the downregulation of major histocompatibility complex (MHC) molecules.437,438,439 It also reduces the expression of IL-12 and co-stimulatory molecules such as CD40 in macrophages and CD80, CD83, and CD86 in DCs to interfere in APC-mediated immune cell activation.440,441 Apart from antigen presentation, TGF-β also inhibits the cytotoxicity of macrophages, on one hand, through the downregulation of cytotoxic factors, such as TNF-α and nitric oxide (NO),442,443,444,445,446 on the other hand, by suppressing the activity of Fcγ receptors (FcγRs) which function to mediate the ADCC and ADCP of macrophages.447 Moreover, TGF-β can trigger the polarization of macrophages and neutrophils from classical M1 macrophages and N1 neutrophils to alternative M2 macrophages and N2 neutrophils which are characterized by multiple immunosuppressive properties.439,448,449,450
TGF-β signaling in disease
Dysfunctional TGF-β signaling can play key roles in numerous pathological processes, contributing to the disorders of developmental defects, aberrant healing, fibrotic diseases, inflammatory diseases, infectious diseases, as well as tumors (Fig. 6).
Developmental defects
Loss of TβRI or TβRII functions due to homozygous mutations generally results in embryonic lethality in mice due to defects in the hematopoiesis and vasculogenesis of yolk sac.451,452 However, the lack of different TGF-β isoforms can lead to distinct phenotypes in mice, consistent with the isoform-specific roles of TGF-β in embryonic development. TGF-β1-knockout mice show no gross developmental abnormalities in spite of the defective hematopoiesis and vasculogenesis in yolk sac during embryonic development.452,453,454 In contrast, TGF-β2-knockout mice exhibit perinatal mortality and a wide range of developmental defects in heart, lungs, bones, eyes, inner ears, craniofacial structures, urogenital organs, and hair follicles.290,455,456,457,458 TGF-β3-knockout mice also die shortly after birth but show no detectable abnormalities except for cleft palate and abnormal lung development.459,460 Notably, palatal shelves that fail to elevate in TGF-β2-knockout mice undergo elevation in TGF-β3-knockout mice but still fail in fusion.455,459,460 Also, branching morphogenesis and respiratory epithelial cell differentiation which appear normal in the lungs of TGF-β2-knockout mice are defective in TGF-β3-knockout mice.455,459 In humans, loss-of-function mutations of a single TGF-β signaling component such as TGF-β2,461,462,463 TGF-β3,464,465,466 TβRI,467,468,469 TβRII,470,471,472 SMAD2,473,474,475 or SMAD3476,477,478 can cause Loeys-Dietz syndrome (LDS), an autosomal dominant connective tissue disorder with a range of cardiovascular, skeletal, craniofacial, and cutaneous manifestations. LDS patients typically present with features including congenital heart defects, aneurysms, arterial tortuosity and dissections, skeletal overgrowth, cervical spine instability, clubfoot deformity, craniosynostosis, hypertelorism, bifid uvula, cleft palate, thin skin, and mental retardation. Dermal fibroblasts derived from LDS patients demonstrate impaired deposition of extracellular collagen and elastin, suggesting a possible mechanism of the connective tissue defects of the patients.479,480 However, the aortic tissues of LDS patients show increased accumulation of collagen, elevated expression of connective tissue growth factor (CTGF), and enhanced activity of non-mutant TGF-β signaling components.461,462,463,465,467,468,475,476,481,482 Therefore, primary downregulation and compensatory upregulation of TGF-β signaling are both responsible for the abnormalities of LDS.
Excessive TGF-β signaling can also act as a primary pathogenic factor in developmental defects. In mice, overexpression of TGF-β or SMAD can lead to developmental abnormalities in several tissues, such as skin,483,484 bones,485 eyes,486 lungs,487,488 mammary glands,489,490,491 salivary glands,492 and central nervous system.493 In humans, Camurati-Engelmann disease (CED), a progressive bone dysplasia inherited in an autosomal dominant manner, is ascribed to mutations of TGF-β1, which lead to increased TGF-β1 activation and signaling.494,495 This disease is characterized by hyperostosis and sclerosis of the long bones and the skull.496,497 Studies on CED have suggested that hyperactive TGF-β1 in the bone microenvironment can induce osteoclasts and osteoblasts to increase but cluster in separated areas, uncoupling bone resorption and formation to cause bone remodeling defects.494,498,499
Aberrant healing and fibrotic diseases
Dysregulated TGF-β signaling can contribute to the tissue damage in aberrant healing and fibrotic diseases which are caused by all kinds of injuries such as wounding, burns, radiation, infection, and inflammation.
Aberrant healing
The lack of TGF-β and TβR expression is commonly found in the chronic wounds in patients, indicating that deficient TGF-β signaling may lead to wound chronicity and even unhealing.500,501,502,503,504,505 However, in vivo studies in mice have reported quite complicated findings. An activating mutation of TβRI can lead to a regenerative healing phenotype which enables rapid regeneration of normal tissues with differentiated structures instead of scar formation in ear punch wounds.506 Paradoxically, overexpression of TGF-β1 in keratinocytes accelerates the re-epithelialization in partial-thickness cutaneous wounds but slows that of full-thickness cutaneous wounds.507,508 In TGF-β1-deficient mice, the healing of full-thickness cutaneous wounds is initially normal but ultimately damaged by severe inflammatory diseases.509 In immunodeficient mice without inflammatory diseases, the lack of TGF-β1 still leads to significant delays in each healing stage of full-thickness cutaneous wounds.510 However, loss of TGF-β signaling in keratinocytes due to expression of dominant negative TβRII leads to increased proliferation and reduced apoptosis, thus facilitating the re-epithelialization in full-thickness cutaneous wounds.511 Furthermore, cutaneous wound healing is accelerated in mice lacking SMAD3 but is aberrant in mice lacking SMAD4 exclusively in keratinocytes.512,513
In contrast to chronic wounds, hypertrophic scars and keloids both characterized by overabundant ECM deposition are the results of hyperactive cutaneous wound healing. In fact, the expression of TGF-β and TβR which decreases eventually in normal cutaneous wounds remains elevated in hypertrophic scars and keloids.514,515,516,517,518 In contrast to normal cutaneous fibroblasts, both keloid fibroblasts and hypertrophic scar fibroblasts are significantly higher in collagen production, however, only keloid fibroblasts exhibit increased sensitivity to TGF-β stimulation.519 For keloid fibroblasts, overexpressed TGF-β can promote the resistance to apoptosis, the ability of proliferation, the conversion to MFs, and the expression of CTGF and VEGF, thus contributing to the ECM deposition, focal adhesion, fibrous growth, and angiogenesis in keloid tissues.518,520,521,522,523
Fibrotic diseases
Besides wounding, other forms of injurious stimulation can also cause excessive ECM deposition in different kinds of tissues, leading to fibrotic diseases, which are closely associated with the hyperactivity of TGF-β signaling.
TGF-β expression is significantly elevated in fibrotic lungs in various cases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF).524,525,526,527,528 In situ hybridization and immunohistochemical staining suggest that alveolar macrophages and epithelial cells are likely the major sources of TGF-β which contribute to the fibrosis of lungs.526,527,528 In vitro studies show that TGF-β1 can trigger the EMT of alveolar epithelial cells and enhance the activity of lung fibroblasts to mediate fibrogenic effects.529,530,531,532 Transgenic expression of TGF-β1 in murine and rat lungs induces pulmonary fibrosis which is accompanied by alveolar EMT, MF differentiation, and mononuclear-rich inflammation.532,533,534,535 Interestingly, the suppression of TGF-β1, the deletion of TβRII, the ablation of SMAD3, the upregulation of SMAD7, but the administration of TGF-β3 can all significantly protect mice from experimentally induced pulmonary fibrosis.535,536,537,538,539
Similarly, the fibrotic kidneys of human glomerulonephritis, IgA nephropathy, diabetic nephropathy, lupus nephritis, as well as renal allografts in chronic rejection all show significant increases in three TGF-β isoforms in the glomeruli and tubulointerstitium where ECM deposition and PAI-1 production is closely related to the expression of TGF-β1 isoform in particular.540,541,542,543 In vitro, TGF-β1 stimulates kidney fibroblasts, mesangial cells, glomerular epithelial cells, and tubular epithelial cells to produce several ECM components and remodelers such as collagen, fibronectin, laminin, proteoglycan, MMP, and TIMP.544,545,546,547,548,549,550 TGF-β1 also contributes to the EMT induction and MF differentiation in renal fibrosis.550 Transgenic mice that have increased levels of TGF-β1 in plasma develop progressive renal disease characterized by glomerulosclerosis and tubulointerstitial fibrosis with TIMP overexpression and ECM deposition in sub-endothelial and mesangial locations.551,552
In fibrotic livers, TGF-β1 expression increases markedly with fibrogenic activity.553,554,555,556 Induction of TGF-β1 expression in murine livers leads to hepatic fibrosis characterized by prominent ECM deposition in peri-sinusoidal areas with activation of HSCs and apoptosis of hepatocytes.557,558 Notably, activated HSCs which play a major role in hepatic fibrosis can provide an important source of TGF-β,559 while overproduced TGF-β can in turn activate several signaling pathways such as those of SMAD, MEK, JNK, PI3K, and JAK/STAT in HSCs to contribute to their functions.236,237
As for the cardiovascular system, TGF-β is also elevated during myocardial fibrosis, valve fibrosis, and arteriosclerosis, generally attributed to the expression by SMCs, fibroblasts, endothelial cells, and inflammatory cells such as macrophages.560,561,562,563,564,565,566,567,568,569 On one hand, TGF-β can stimulate cardiovascular fibroblasts to differentiate into MFs and produce ECM components and remodelers,562,563,570,571,572,573 on the other hand, it can also stimulate endothelial cells to undergo EndMT to induce their fibrogenic phenotype.569,574,575
Furthermore, TGF-β is widely involved in the fibrosis of many other tissues and diseases as in the cases of cutaneous fibrosis,576,577 muscular fibrosis,578 pancreatic fibrosis,579,580,581,582 myelofibrosis,583,584 adenomyosis,585 autoimmune diseases,238,527,573,586,587,588,589 and infectious diseases.590,591,592,593
Inflammatory diseases and infectious diseases
Inflammatory diseases and infectious diseases can demonstrate aberrant immune responses and various tissue injuries which usually implicate the dysfunction of TGF-β signaling.
Inflammatory diseases
Since TGF-β acts as a negative regulator to maintain immune homeostasis, deficient TGF-β signaling can lead to hyperactive immune responses, contributing to the pathology of numerous inflammatory diseases. TGF-β1-null mice initially appear normal after birth but soon develop a rapid wasting syndrome accompanied by a multifocal inflammatory disease which leads to organ failure and early death by 3-4 weeks of age.453,594,595,596 Many organs in these mice, including heart, lungs, stomach, liver, pancreas, and muscles, all exhibit massive infiltration of inflammatory cells such as lymphocytes, macrophages, and granulocytes. Moreover, their total numbers of blood leukocytes increase mainly due to the elevated absolute numbers of neutrophils and monocytes, while their levels of autoantibodies, MHC molecules, and inflammatory cytokines such as IFN-γ, TNF-α, and CCL3 also rise correspondingly in serum or tissues.
In the absence of any pathogens, the inflammatory diseases in TGF-β1-knockout mice actually resemble a special group of inflammatory diseases known as autoimmune diseases, which are characterized by dysregulated immune responses attacking self-tissues. In fact, even cell type-specific loss of TGF-β signaling can lead to the development of various autoimmune diseases in mice.597,598,599,600,601,602,603,604 In patients with autoimmune diseases such as systemic lupus erythematosus (SLE),605,606,607 systemic sclerosis (SSc),608,609,610,611 rheumatoid arthritis (RA),612,613,614 Sjögren’s syndrome,586,614,615,616 Crohn’s disease,587,617,618,619 ulcerative colitis (UC),617,618,619,620,621,622 autoimmune hepatitis (AIH),623,624 and Hashimoto’s thyroiditis (HT),606,625,626 the levels of TGF-β or TβR in tissues or circulation are associated with the presence, activity, and severity of the diseases. Notably, although all these diseases show correlations with dysregulated TGF-β signaling, their correlations with TGF-β levels can be either positive or negative. Some cases of the diseases are likely caused by insufficient TGF-β expression and thus exhibit decreased TGF-β production.619,622,627,628,629,630 In other cases, however, the autoimmune inflammation is likely attributed to impaired cell responsiveness to TGF-β especially due to deficient TβR functions, therefore, TGF-β production is elevated as a compensatory response.624,628,631,632,633,634,635
Allergic diseases, including asthma, allergic rhinitis, food allergy, and atopic dermatitis, are another group of inflammatory diseases that are caused by aberrant immune responses to harmless environmental antigens. TGF-β production is increased in the airways and serum of asthmatic patients and is further increased after allergen exposure, disease progression, or certain treatments.636,637,638,639,640,641,642,643,644,645,646 Bronchial epithelial cells, fibroblasts, SMCs, eosinophils, neutrophils, and macrophages can all contribute to the excessive TGF-β production in asthmatic patients.641,642,643,644,645,646,647,648,649,650 However, the functions of TGF-β are seemingly contradictory in the context of allergic airway inflammation, for TGF-β can either enhance or suppress the activity of eosinophils, lymphocytes, macrophages, and mast cells in asthma.648,651,652,653,654,655,656,657,658,659,660,661 Nevertheless, it is clear that TGF-β can promote asthmatic airway remodeling by inducing airway EMT,662,663 ECM production,649,650 MF differentiation,664,665 and smooth muscle hyperplasia.647 In patients with allergic rhinitis, TGF-β levels in serum are found dependent on allergen exposure, while TGF-β and TβR expression in nasal mucosa is noticed correlated with intra-epithelial mast cell abundance.666,667,668 In fact, allergen challenge can activate TGF-β signaling in the mast cells and epithelial cells in nasal mucosa which may contribute to the mast cell accumulation and goblet cell hyperplasia in allergic rhinitis.669,670 Allergen challenge can also induce the loss of TGF-β1-expressing Bregs and Tregs which function to suppress the inflammatory Th2 responses of allergic rhinitis. However, with prolonged challenging time, the proportion of TGF-β1-expressing Bregs and Tregs can gradually recover to reconstitute the immune homeostasis in nasal mucosa.671 Similarly, TGF-β can inhibit the Th2 responses of food allergy by promoting Treg activity in the intestines.603,672,673 Therefore, reduced TGF-β1 expression in the intestinal epithelial cells and mononuclear cells of patients with food allergy can partially account for the development of the disease.603,674 Moreover, TGF-β can inhibit the pathology of atopic dermatitis by suppressing B cell maturation, mast cell activation, eosinophil infiltration, as well as the secretion of IgE, TNF-α, and histamine by those cells.675,676,677 Aberrant TGF-β expression or attenuated cell responsiveness discovered in patients with atopic dermatitis may play a key role in the disorder.678,679,680
Furthermore, TGF-β signaling is implicated in the pathology of other inflammatory diseases and inflammation-related diseases such as bronchitis,642 pancreatitis,681,682,683 glomerulonephritis,684,685 osteomyelitis,686 arthritis,687 diabetes,688 and Alzheimer’s disease (AD).689,690
Infectious diseases
Infectious diseases caused by different kinds of pathogenic organisms can result in tissue damage due to diverse pathogen virulence and dysregulated host responses.
TGF-β can function to reduce pathogen burdens as well as tissue injuries in some cases of infection. In patients with H1N1 influenza A virus sepsis, blood TGF-β levels are negatively correlated with clinical severity scores on admission.691 Consistently, increased TGF-β activity in mice confers resistance against lethal influenza infection due to reductions in both viral titers and pulmonary inflammation.692,693 TGF-β expression also prevents mice from coxsackievirus-induced myocarditis and type 1 diabetes in a Treg-dependent manner.694,695 Moreover, TGF-β acts as a pro-survival factor to protect murine neurons and intestinal epithelial cells against cell death during reovirus infection.696,697 As for bacterial infection, TGF-β can attenuate sepsis-induced tissue injuries through mechanisms involving the induction of Tregs.698 It also enhances the pathogen clearance and host resistance of mice during the infection of Streptococcus pneumoniae,699 Streptococcus pyogenes,700 Listeria monocytogenes,701 and Yersinia enterocolitica,702 likely, by suppressing IFN-γ, TNF-α, and IL-6 production while promoting Th17 and Treg responses. In rats with pulmonary cryptococcosis, TGF-β reduces fungal burdens by promoting the lysozyme secretion of macrophages, meanwhile, it also limits inflammation by inhibiting macrophage phagocytosis, chemokine production, and oxidative burst.703 Moreover, TGF-β can be protective during parasitic infection. The lack of TGF-β exacerbates the severity of murine malaria infection, whereas TGF-β treatment, in contrast, suppresses plasmodium proliferation and prolongs mice survival with decreased TNF-α and increased IL-10 in serum.704 During Trypanosoma congolense infection, exogenous TGF-β1 confers early protection against parasitemia, anemia, splenomegaly, and mortality due to enhanced macrophage activity and Th1 responses which are characterized by increased NO, IFN-γ, TNF-α, IL-12, and IgG2a production.705 During Toxoplasma infection, TGF-β can prevent tissue damage by reducing inflammatory cell infiltration and cytokine production, while it can also improve the outcomes of infection-related abnormal pregnancy by promoting Treg functions and suppressing NK cytotoxicity.706,707,708,709 Furthermore, TGF-β can prevent the lung injuries during hookworm infection by inducing the immunosuppressive activity of myeloid cells to reduce Th2 responses.710
In other cases of infection, however, TGF-β can turn to facilitate pathogen infection and tissue injuries. In clinical patients, circulating TGF-β1 levels are positively correlated with the severity and mortality of severe community-acquired pneumonia (CAP)711 and sepsis-induced acute respiratory distress syndrome (ARDS).712 Increased TGF-β production can impair the anti-bacterial functions of neutrophils, uncouple the cytokine production and glycolysis of macrophages, and suppress the IL-2 expression and proliferation of T cells to participate in the pathology of sepsis.713,714,715 As for bacterial infection in local tissues, on one hand, TGF-β can upregulate fibronectin and integrins in hosts to promote bacterial adhesion and invasion,716,717 on the other hand, it can attenuate anti-infectious innate responses and Th1 responses while inducing immunotolerant Treg responses to facilitate the immune escape of the pathogens.718,719,720,721,722 TGF-β-mediated immunosuppression can also contribute to viral infection, as elevated TGF-β expression during viral infection not only impairs early innate immunity such as IFN responses, NK functions, and macrophage activity but also suppresses the adaptive immune responses of T cells and B cells.428,723,724,725,726,727,728,729,730,731 Notably, TGF-β can also enhance viral infection through certain pathogen-specific mechanisms as in the cases of human immunodeficiency virus type 1 (HIV-1) infection,732,733,734 human T-cell leukemia virus type I (HTLV-I) infection,735 hepatitis C virus (HCV) infection,736 Zika virus (ZIKV) infection,737 as well as rubella virus (RuV) infection.738 Furthermore, TGF-β can promote the survival and growth of parasites in hosts through downregulation of NO, IFN-γ, TNF-α, IL-6, IL-17, and Th17 cells as well as upregulation of IL-4, IL-10, and Treg cells, contributing to the infection of Fasciola hepatica,739 Echinococcus multilocularis,740 Toxoplasma gondii,741 Leishmania,742 and Plasmodium.743,744
Tumors
It is generally accepted that TGF-β acts as a tumor suppressor during the early stages of tumorigenesis but turns into a tumor promotor at later stages of tumor development.
Tumorigenesis
Evidence from animal models firmly establishes the suppressor role of TGF-β signaling in early tumorigenesis. TGF-β and its receptors can be strongly induced in the murine epidermis upon exposure to carcinogens that tend to disrupt tissue homeostasis and cause oncogenic transformation.745,746 Increased TGF-β expression in murine epidermis can potently attenuate cell proliferation and confer resistance to hyperproliferation induced by carcinogens.316,746,747 Similarly, in murine mammary epithelia, the overexpression of TGF-β or TβR can result in remarkable protection from carcinogen-induced tumorigenesis with reduced premalignant lesions, prolonged tumor latency, and decreased cancer incidence.25,491,748,749,750 Such tumor-inhibitory effects by TGF-β signaling are attributed to the early apoptosis of differentiating cells and, more importantly, the premature senescence of stem cells which reduces the reproductive capacity of the mammary epithelia and thus decreases the frequency with which transforming mutations may occur and be fixed in the cell population.491,748
In contrast, loss of TGF-β signaling can be an early event that contributes to tumorigenesis. In clinical patients, heterogeneous patterns of TβRII expression in normal breast lobular units as well as loss of TβRII expression in breast epithelial hyperplastic lesions are both associated with increased risks of invasive breast cancer.751 More convincing evidence is provided by germline mutations of TGF-β signaling components which show strong correlations with increased risks of tumorigenesis. Loss-of-function TβRI mutations can result in an autosomal dominant skin cancer condition known as multiple self-healing squamous epithelioma (MSSE) or Ferguson-Smith disease (FSD) which is characterized by multiple squamous-carcinoma-like skin tumors that invade locally and then regress spontaneously after several months.752,753 Inactivating TβRII mutations are considered causative of some cases of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, an autosomal dominant cancer predisposition syndrome, by impairing cell growth inhibition in response to TGF-β.754 Moreover, germline mutations of SMAD4 are responsible for juvenile polyposis, an autosomal dominant syndrome predisposing to gastrointestinal hamartomatous polyps and cancers.755,756 Mechanically, impaired TGF-β signaling can cause serious disturbance to tissue homeostasis, thus largely facilitating the development of pre-neoplastic lesions, as well as subsequent tumors, as shown in different murine tissues with deficiencies in the activity of TGF-β,757,758 TβR,749,759,760,761,762,763,764,765,766,767,768,769,770 or SMAD.657,771,772,773,774,775,776 Among them, TβR-deleted murine epithelia exhibit significant reductions in p15 and p21 and remarkable increases in MYC expression and RAS/ERK signaling, accompanied by elevated cell proliferation, reduced cell apoptosis, and enhanced cell malignant transformation to become tumorigenic.762,763,764,765
Furthermore, TGF-β can provide additional protection against tumorigenesis by controlling pathogen infection,777 inhibiting excessive inflammation,778,779,780,781 reducing genomic instability,782 inducing replicative senescence,783 and regulating epithelial-mesenchymal interaction.784
Tumor growth
TGF-β can inhibit tumor growth by triggering cytostasis and apoptosis through similar mechanisms as it does in cells from normal tissues. In tumor cells, TGF-β signaling induces cell cycle arrest by targeting effectors, such as p15,354,356 p21,355,785,786 p27,361 MYC,363 ID,787 and CDC25A,374,786 while it also induces apoptotic cell death through effectors including CTGF,788 programmed cell death 4 (PDCD4),789 Fas receptor,790 death-associated protein kinase (DAPK),791 DAXX,383 IκB-α,384,386 sex-determining region Y (SRY)-box 4 (SOX4),792 ARTS,382 TIEGs,793 as well as several BCL-2 family members.794,795,796,797,798,799,800 Consistently, primary tumors induced from murine tissues with intact TGF-β signaling pathways are initially responsive to TGF-β-mediated inhibitory effects.491,749,759,764,801,802
On the contrary, deficient TGF-β signaling can potently promote the growth of tumors. The downregulation of tumor TGF-β signaling in many cases is attributed to reduced expression or inactivating mutations of TβR or SMAD, as shown in various tumor types such as leukemia,772 lymphoma,803,804 esophageal cancer,805,806,807 gastric cancer,808 colorectal cancer,30,807,809,810,811 pancreatic cancer,32,812,813 biliary cancer,812 ampullary cancer,814 thyroid cancer,815 prostate cancer,816,817 breast cancer,818 ovarian cancer,819 endometrial cancer,808 genital squamous cell carcinomas (SCC),764 head and neck SCC,820,821,822,823 etc. These changes are able to confer resistance to the tumor-inhibitory effects of TGF-β. In mouse models, tumors developed from tissues with deletion or inactivation of TβR exhibit increased cell proliferation and decreased cell apoptosis, accompanied by reduction in p15, p21, and p27, the elevation of MYC, cyclin D1, and epidermal growth factor receptor (EGFR), as well as activation of STAT3 and PI3K/AKT pathways.761,762,763,764,765 Interestingly, reconstituted expression of TβRII in tumor cells with corresponding deficiency not only restores the inhibitory responses to TGF-β but also significantly attenuates the tumorigenicity of these cells.824
Notably, TGF-β can fail to suppress the growth of tumors where there is likely no loss of functional TGF-β signaling components, and even formerly inhibited tumor cells can subsequently resume proliferating in vitro and develop larger tumor masses in vivo.354,825,826 On one hand, such resistance may result from the dysfunction of the downstream targets of TGF-β signaling such as CKIs.354 On the other hand, the tumor-suppressive signaling of TGF-β can be offset or interfered by enhanced I-SMAD activity827 or potent oncogenic factors such as E1A,828,829 EVI1,148,830 SKI,150,152 SNO,153 MYC,831 ID2,832 mutant p53,833 as well as RAS/RAF/ERK signaling.162,834 Moreover, TGF-β-mediated tumor-promoting effects can also account for the enhanced tumor growth in vivo, as discussed in a later section.
Tumor invasion and metastasis
Contrary to its role as a suppressor of tumor growth, TGF-β generally acts as a promoter of tumor invasion and metastasis especially in advanced tumors. Upregulation of TGF-β as well as its receptors is associated with disease progression and poor prognosis in some patients with tumors such as breast cancer,835,836 pancreatic cancer,837,838 and gastric cancer.839 Consistently, TGF-β overexpression or pre-treatment enables tumor cells to form increased metastases in vivo,825,840 while loss of TGF-β responsiveness due to the introduction of dominant negative TβRII decreases the metastatic efficiency of high-grade tumor cells.841,842 Moreover, tumors derived from transgenic murine epithelia that overexpress TGF-β or TβR are significantly more malignant and more invasive.491,749,750,802,843 Notably, these TGF-β-overexpressing tumor cells are more likely to undergo the transition from epithelial cell phenotype into spindle cell phenotype which is the most malignant and invasive cell type.802,843 This indicates that TGF-β can facilitate the progression of epithelial-derived tumors through the induction of EMT which is inoperative in tumors with deficiencies in TβR or SMAD.761,770,774,842,843 Similar to the EMT of normal cells, TGF-β-induced EMT of tumor cells is characterized by changes in keratin, integrin, cadherin, catenin, claudin, vimentin, occludin, fibronectin, and MMP expression which can contribute to the invasive and metastatic capacity of tumors.197,198,200,203,230,232,750,774,802,843,844,845,846,847,848
However, loss of functional TGF-β signaling components can occur in tumor cells during disease progression.759,809 In fact, reduced TGF-β signaling can also contribute to tumor invasion and metastasis. For some patients, decreased expression of TβR is correlated with higher tumor grades, later clinical stages, and worse clinical prognosis.805,816,818 A large number of cell models and mouse models also demonstrate that tumors lacking TGF-β signaling tend to be more malignant and more aggressive.758,760,761,762,764,801,841,843,849,850,851,852 Relevant mechanisms in these cases involve the loss of E-cadherin,761 the reduction in PAI,849 the increase in RHO/RAC signaling,843 the activation of integrin/focal adhesion kinase (FAK)/SRC/MAPK pathway,764 and more importantly, the overexpression of various pro-invasive and pro-metastatic factors. In mouse models, deficient TGF-β signaling can stimulate tumor cells and stromal cells to produce high levels of TGF-β and other tumor-promoting factors such as CTGF, VEGF, IL-1β, C-X-C motif chemokine ligand (CXCL8), CXCL12, cyclooxygenase(COX)-2, MMPs, collagen, and tenascin C (TNC) which can strongly promote tumor angiogenesis, fibroblasts activation, immune infiltration, and ECM remodeling.760,761,762,763,764,774,843,850
Tumor microenvironment (TME) remodeling
TGF-β can stimulate tumor progression even when its signaling pathways are unavailable in the tumor cells, indicating its additional tumor-promoting effects exerted on tumor stroma.760,761,762,763,764,843 Fibroblasts, endothelial cells, and immune cells are the major stromal cell types in TME and can all be manipulated by TGF-β in favor of tumor progression.
Actively produced TGF-β in the TME can stimulate the chemotactic migration of fibroblasts and convert them into MFs which are also known as cancer-associated fibroblasts (CAFs) in terms of tumors.305,853 Activated CAFs can in turn repay TME with more TGF-β as well as other tumor-promoting factors such as TGF-α, FGF, HGF, PDGF, and CTGF to exert a strong stimulation on tumor growth.324,853,854,855,856,857 Moreover, TGF-β regulates the production of various ECM components and remodelers by CAFs to facilitate the migration of tumor cells during invasion and metastasis.855,858 Interestingly, fibroblasts with the loss of TβRII can also contribute to tumor development through the production of TGF-α, HGF, and macrophage-stimulating protein (MSP).859
Endothelial cells can also be converted into CAFs through TGF-β-mediated EndMT.860 More importantly, TGF-β promotes the angiogenesis of endothelial cells by inducing VEGF production in tumor cells and fibroblasts.323,354,750,861,862 TGF-β also disrupts inter-endothelial junctions to increase the vascular permeability in TME through the process of EndMT and the induction of angiopoietin-like 4 (ANGPTL4).863 Therefore, TGF-β-mediated angiogenesis not only increases the blood supply to tumors to favor their growth but also provides tumors with more accessible entrances into the circulation to form metastasis.
Furthermore, TGF-β can modulate immune cell activity to facilitate tumor survival and development. TGF-β inhibits the tumoricidal activity of macrophages and neutrophils and polarizes them into tumor-promoting M2 macrophages and N2 neutrophils, which are also known as tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) in terms of tumors.439,442,444,448,449,864 It also promotes the functions of Tregs while suppressing the cytotoxicity of CTLs and NK cells to facilitate tumor evasion from immune surveillance.865,866,867,868,869 Moreover, TGF-β can inhibit the expression of MHC antigens in tumor cells to further attenuate their recognition by adaptive anti-tumor immunity.870,871 However, TGF-β-mediated downregulation of MHC antigens and NKG2D ligands can increase tumor susceptibility to NK cytotoxicity to some extent.233,872
TGF-β-targeting therapies
To rectify the dysfunction of TGF-β in different kinds of diseases, several targeted therapies have been developed to regulate TGF-β activity at the levels of biosynthesis, activation, and signaling. Many completed clinical trials have preliminarily confirmed the safety and efficacy of some therapeutic strategies, while there are still numerous clinical trials ongoing at present (Table 1).
Alteration of TGF-β biosynthesis
Targeting TGF-β mRNAs
Trabedersen (AP 12009 or OT-101) is an antisense oligonucleotide complementary to human TGF-β2 mRNA and can specifically inhibit TGF-β2 biosynthesis. It is hypothesized that trabedersen mainly acts by reversing TGF-β2-mediated immunosuppression to facilitate immune responses against tumors. A phase 2b clinical trial showed no advantage in early tumor control rate but in long-term survival rate for glioma patients treated with trabedersen in comparison with standard chemotherapy. Tumor responses which continued to increase long after discontinuation in the study suggested that the clinically relevant beneficial effects of trabedersen might increase over time. Moreover, compared with the standard chemotherapy group, drug-related or possibly drug-related adverse events in the trabedersen group were less common and mostly nervous system disorders. The study also indicated that the optimal dose of trabedersen is 10 µM, as both its efficacy and safety tended to be superior to the 80 µM dose, although the mechanism for this counterintuitive result has not been fully understood.873 TGF-β1 antisense oligonucleotides or small interfering RNAs (siRNAs) were also developed and evaluated in different pre-clinical models, suggested as potential therapeutic strategies for tuberculosis,874,875 wound scarring,876,877 and several renal diseases.878,879,880,881
TGF-β antisense gene-modified tumor cell vaccines are designed to exhibit increased immunogenicity due to reduced TGF-β expression in the tumor cells that comprise the vaccines. Vaccine Lucanix (belagenpumatucel-L) made from allogeneic non-small cell lung cancer (NSCLC) cell lines was well tolerated and brought survival advantages to NSCLC patients who were randomized within 12 weeks of completion of platinum-based chemotherapy and in those who had received prior radiation, as shown in a phase 3 trial which, however, failed to demonstrate a significant increase in survival in the overall patient population.882 TGF-β antisense-modified autologous tumor cell vaccines have also been tested in advanced glioma and other solid tumors, respectively, in two phase 1 studies in which enhanced anti-tumor activity and improved survival were observed.34,883 Notably, in the study among glioma patients, the most common treatment-related adverse events were delayed-type hypersensitivity-like reactions observed at the sites of the second and subsequent vaccinations in all patients. Some of these patients also experienced transient, flu-like symptoms consisting of musculoskeletal aches and pains and fatigue during the course of treatment.34
Targeting furin
Convertase furin is a therapeutic target participating in the post-translational processing of TGF-β. Vigil (FANG or Gemogenovatucel-T) is an autologous tumor cell vaccine incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a bifunctional short-hairpin RNA (shRNA) targeting the expression of furin. A phase 1 study confirmed its safety and efficacy in various advanced solid tumors, with significant survival differences noted between patients who received less than four vaccinations and those who received no less than four vaccinations.884 A later phase 2b trial also demonstrated significant clinical benefit in homologous recombination proficient ovarian cancer (NCT02346747).885 Both studies reported no treatment-related serious adverse events, while the most common grade one and two adverse events related to study medication were local reactions at the injection site.
Alteration of TGF-β activation
Targeting latent TGF-β complex
SRK-181 is an antibody that selectively binds to latent TGF-β1 to inhibit its activation. Co-administration of SRK-181 and anti-PD-1 antibody induced profound anti-tumor responses and survival benefit in mice, with increased infiltrating CD8+ T cells and decreased immunosuppressive myeloid cells observed in tumors refractory to anti-PD-1 treatment.886 The selective blockade of TGF-β1 by SRK-181 neither caused cardiac valvulopathy in rats as pan-TGFβ inhibitors might do nor did it induce cytokine release in human peripheral blood. Moreover, SRK-181 showed no effect on human platelet aggregation, activation, and binding.886,887 The favorable safety profile displayed in these preclinical assessments supports the ongoing phase 1 trial of SRK-181 in patients with advanced cancers (NCT04291079).
Targeting GARP
GARP expressed by Tregs, platelets, and endothelium functions to tether latent TGF-β complex to the cell surface for activation. Anti-GARP monoclonal antibody PIIO-1 proved to be an effective and safe strategy to block TGF-β activation in preclinical models, for it specifically bound to ligand-free GARP on Tregs but lacked recognition of GARP-latent TGF-β complex on platelets, actually avoiding the risk of platelet-related toxicities such as thrombocytopenia. More importantly, PIIO-1 showed therapeutic efficacy against both GARP+ and GARP- cancers alone or in combination with anti-PD-1 antibody, by preventing T cell exhaustion and enhancing CD8+ T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.888
Targeting αV integrins
Integrins are regarded as the most important activators of TGF-β. Abituzumab (EMD 525797 or DI17E6) is an antibody against pan-αV integrins. In a phase 1/2 trial on KRAS wild-type metastatic colorectal cancer (NCT01008475), the progression-free survival (PFS) and response rates were similar among all groups in the intent-to-treat population comprising all patients randomized, although a trend toward improved overall survival (OS) was observed in the groups that received abituzumab treatment. However, exploratory analysis suggested that in patients with high αVβ6 expression, PFS and response rates might be increased with abituzumab therapy.889 This pan-αV integrin inhibitor was also found to inhibit prostate cancer-associated bone lesion formation in a randomized phase 2 trial (NCT01360840), although PFS was not significantly extended.890 Recently, abituzumab has been investigated in SSc-associated interstitial lung disease in a phase 2 trial (NCT02745145). However, the study was terminated prematurely due to slow enrollment and no meaningful conclusions could be drawn due to a small sample size.891 The most commonly reported treatment-related adverse events of abituzumab included fatigue, headache, gastrointestinal disorders, as well as abnormal biochemistry and hematology values.889,890,892
Cilengitide (EMD 121974, NSC 707544) is a selective αvβ3 and αvβ5 integrin inhibitor which has been evaluated for therapeutic efficacy in NSCLC (NCT00842712),893,894 head and neck SCC (NCT00705016),895 glioblastoma (NCT00689221, NCT00813943, and NCT01124240),896,897,898,899,900,901,902,903 melanoma,904 pancreatic cancer,905 and prostate cancer906,907 in a series of phase 2 studies and one phase 3 study. Although cilengitide failed to demonstrate significant clinical benefits in these studies on tumors, it might be a novel treatment for fibrotic diseases as relevant preclinical studies suggested.908,909 Notably, the adverse events possibly related to cilengitide treatment included fatigue, arthralgia, lymphopenia, and gastrointestinal disorders.893,897,899,900,904,906,907 Furthermore, an inhibitor of pan-integrins and TGF-β known as GLPG-0187 was proved to enhance T cell killing of colorectal cancer cells in vitro, possibly by suppressing TGF-β-mediated PD-L1 upregulation.910,911
Targeting TSP-1
TSP-1 can directly activate all three TGF-β isoforms independent of other activators or cellular activity. The conserved LSKL sequence in LAP which is recognized by TSP-1 can be synthesized as peptides to block TSP-1-mediated TGF-β activation. Pre-clinical studies suggested that treatment of LSKL or relevant tripeptide SRI31277 could be novel therapeutic strategies for various cardiovascular diseases,912 pulmonary diseases,913 renal diseases,914,915,916 nervous diseases,917,918 fibrotic diseases,919,920,921 wound healing,922,923 and tumors.924,925,926 Moreover, TSP-1 antisense oligonucleotides were successfully developed and applied to inhibit TGF-β activation in a rat model of mesangial proliferative glomerulonephritis, demonstrating a remarkable prevention against renal fibrosis.927
Alteration of TGF-β signaling
Targeting TGF-β ligands
A TGF-β2-enriched polymeric dietary supplement known as Modulen (CT3211) was effective in inducing earlier remission of inflammatory bowel diseases (IBDs) including both Crohn’s disease and UC with significant improvements in endoscopic and histologic appearances, mucosal cytokine parameters, C-reactive protein (CRP) values, erythrocyte sedimentation rates (ESRs), serum albumin levels, as well as weight and height scores in the patients.928,929,930,931 Notably, an exclusive Modulen diet was more efficient than steroids to induce mucosal healing in children with Crohn’s disease, possibly due to its additional advantage in regulating intestinal microbiota (NCT00265772).932,933 Moreover, a pre-operative polymeric diet enriched with TGF-β2 was able to decrease post-operative complications after surgery for complicated ileocolonic Crohn’s disease.934 The side effects of Modulen were mild, including abdominal pain, flatulence, nausea, and vomiting.928,932,934 In mouse models, oral TGF-β supplementation also showed beneficial effects on food allergy prevention.935,936,937 In fact, it is believed that the presence of TGF-β in breast milk can protect the progeny from several allergic diseases such as asthma,938 eczema,939 and food allergy.940
Recombinant human TGF-β3 known as avotermin (Juvista) is a potential therapy for the improvement of cutaneous scarring. In a series of phase 1/2 studies (NCT00847925, NCT00847795, NCT00629811, NCT00432211, NCT00594581, and NCT00430326), visual assessment of scar formation revealed that, in contrast to placebo, intradermal avotermin could significantly improve total scar scores which were derived from a visual analog scale to assess how closely scars resembled normal skin. The results were further confirmed by histological assessments that scars treated with avotermin showed better organized ECM of the papillary and reticular dermis. The incidence of adverse events at wound sites, including infection, exudate, erythema, pain, burning, itching, and thickening was low and similar for avotermin and controls.941,942,943,944 Although the other two TGF-β isoforms, TGF-β1 and TGF-β2, showed no therapeutic activity of scarring, they were found to improve and accelerate the healing of cutaneous wounds in animal models as well as clinical patients.304,306,307,317,321,334,945 Moreover, TGF-β also showed therapeutic potential for tissue regeneration,329,946,947 inflammatory diseases,676,687,948 and influenza949 as shown in relevant preclinical models.
TGF-β neutralizing antibodies and ligand traps can block the binding of TGF-β to its receptors. Fresolimumab (GC1008), a monoclonal antibody that neutralizes all three TGF-β isoforms demonstrated acceptable safety and preliminary evidence of anti-tumor activity in a phase 1 study on advanced malignant melanoma and renal cell carcinoma (NCT00356460).950 In a phase 2 trial (NCT01401062), a higher dose of fresolimumab is associated with longer median OS as well as improved peripheral blood mononuclear cell counts and boosted central memory CD8+ T cell levels in metastatic breast cancer patients receiving radiotherapy.951 Fresolimumab also showed therapeutic effects on SSc with decreased biomarkers of skin fibrosis and improved clinical symptoms in the patients in a phase 1 study (NCT01284322).952 Moreover, a phase 1 study evaluated the safety of fresolimumab in patients with treatment-resistant primary focal segmental glomerulosclerosis and the good tolerability supported additional evaluation in larger randomized dose-ranging clinical trials.953 Notably, the major drug-related adverse events of fresolimumab were skin disorders, bleeding episodes, and anemia. Skin toxicity was particularly significant and tumor patients assigned to high doses of treatment even developed skin tumors, including keratoacanthoma, basal cell carcinoma, and SCC.950,951,952,953,954 Another anti-TGF-β monoclonal antibody known as NIS793 was well tolerated alone or in combination with anti-PD-1 antibody in patients with advanced solid tumors in a phase 1 study (NCT02947165). Treatment-related adverse events of all patients in the study were mostly skin toxicity and gastrointestinal events, and no dose-limiting toxicities were observed during dose escalation. Notably, biomarker analyses in the study showed evidence of systemic target engagement, local signaling inhibition, and tumor immune activation.955 Apart from tumors, a recombinant human anti-TGF-β1 antibody known as CAT-192 was evaluated in the treatment of early-stage diffuse cutaneous SSc but showed no evidence of efficacy in the pilot phase 1/2 study. The most commonly reported adverse events in the study affected the gastrointestinal, musculoskeletal, respiratory, and skin systems, but none of them were considered to be related to the treatment.956 Moreover, a phase 2 study assessing the safety and efficacy of TGF-β1 monoclonal antibody in patients with diabetic nephropathy was terminated early for futility (NCT01113801). The frequencies of the various categories of adverse effects in this study were generally similar between the treatment and placebo groups.957 Furthermore, monotherapy of a selective TGF-β1/3 trap known as AVID200 in a population of patients with an advanced stage of myelofibrosis in a phase 1b trial resulted in limited toxicity as well as improvements in spleen size, symptom benefit, and platelet counts (NCT03895112). Remarkably, platelet count increase was a therapeutic effect not observed with other myelofibrosis therapies, suggesting a potential advantage of AVID200 treatment. Adverse events that occurred during the study regardless of attribution mainly included pruritus, fatigue, abdominal pain, anemia, and thrombocytopenia.958 Additionally, other potential applications of neutralizing TGF-β antibodies suggested by pre-clinical studies include wound healing,334,959,960 prostatic hyperplasia,961 pulmonary diseases,962,963 cardiovascular diseases,564,964 musculoskeletal diseases,965,966,967,968 inflammatory diseases,969,970 and Chagas disease (Trypanosoma cruzi infection).971
Bifunctional antibody-ligand traps containing the extracellular domain of TβRII can target both TGF-β and immune checkpoints. In preclinical studies, both the anti-CTL associated protein (CTLA)-4-TβRII chimera and the anti-PD-L1-TβRII chimera exhibited superior anti-tumor efficacy compared with their parent immune checkpoint inhibitors.972 Bintrafusp alfa (M7824), a bifunctional fusion protein targeting both TGF-β and PD-L1 was assessed in several phase 1 trials (NCT02699515, NCT02517398, NCT02699515, and NCT04247282). The results showed that bintrafusp alfa had encouraging efficacy in NSCLC,973 gastric cancer,974 biliary tract cancer,975 as well as human papillomavirus (HPV)-unrelated head and neck cancer in which enhanced tumor antigen-specific immunity has been observed.976 Similar to fresolimumab, the treatment-related adverse events of bintrafusp alfa included fatigue, colitis, bleeding, anemia, hypokalemia, lipase increase, hepatic function abnormalities, as well as several skin disorders from rash, hyperkeratosis, to keratoacanthoma and SCC.973,974,975,976,977 BR102 is another bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. The efficacy and safety of BR102 demonstrated in preclinical characterization supported its further clinical development for anti-cancer therapy.978 Notably, the bifunctional antibody-ligand traps have inspired the development of chimeric antigen receptor (CAR)-T cells secreting bispecific trap protein, which co-targets PD-1 and TGF-β to enhance anti-tumor efficacy as shown in mouse models.979
Furthermore, LAP, TβRIII (β-glycan), and decorin can bind to TGF-β as natural inhibitors. They have shown treatment effects in preclinical models of wound healing,980,981,982,983 cardiovascular diseases,984,985,986,987,988,989 nervous diseases,990,991,992 renal diseases,993,994,995,996 fibrotic diseases,997,998,999,1000 tuberculosis,1001 and tumors1002,1003,1004,1005 and thus warrant further development.
Targeting TβRs
TGF-β-insensitive CAR-T cells armored with dominant-negative TβRII showed preliminary evidence for early anti-tumor function in prostate cancer, including a biomarker decline among approximately 30% of the patients in a phase 1 trial (NCT03089203). This strategy which is considered generally feasible, despite no partial response being observed in the study, and safe, with study-related serious adverse events mostly being cytokine release syndrome, warrants further validation and investigation.1006 Dominant-negative TβRII can also enhance the anti-tumor efficacy of DC vaccines, manifested by powerful tumor-specific CTL responses, inhibited tumor development, and prolonged survival times in mouse models.1007,1008 Moreover, dominant-negative TβRII showed great potential for reducing hypertrophic scars as in rabbit ear models.1009
Many small-molecule inhibitors have been developed to suppress the kinase activity of TβRI. In a series of phase 2 studies, a TβRI kinase inhibitor known as galunisertib (LY2157299) showed preliminary efficacy in patients with myelodysplastic syndromes (MDS) (NCT02008318),1010 NSCLC (NCT02423343),1011 hepatocellular carcinoma (NCT01246986),1012,1013 rectal cancer (NCT02688712),1014 and pancreatic cancer,1015 but failed to demonstrate clinical benefit in patients with glioma (NCT01582269 and NCT01220271).1016,1017 The most common adverse events related to galunisertib treatment included fatigue, pyrexia, anemia, nausea, vomiting, diarrhea, and abdominal pain.1010,1013,1017 Despite comprehensive cardiovascular monitoring for galunisertib did not detect medically relevant cardiac toxicity in cancer patients,1018 galunisertib-related uncontrolled cytokine release was reported in patients with advanced solid tumors in a phase 1 trial (NCT01646203).1019 Other TβRI kinase inhibitors such as SM16, SD-208, NP-40208, SB-431542, LY3200882, LY364947, and vactosertib (EW-7197) also showed therapeutic potential in pre-clinical studies on tumors1020,1021,1022,1023,1024,1025,1026 as well as many other diseases such as cardiovascular diseases,565,1027,1028,1029,1030 renal diseases,1031 ophthalmic diseases,1032 skeletal diseases,1033 fibrotic diseases,1034,1035,1036 inflammatory diseases,1037,1038,1039 Chagas disease,1040,1041 coronavirus disease 2019 (COVID-19),1042 and wound healing.1043,1044,1045
Targeting SMADs
An oral SMAD7 antisense oligonucleotide known as mongersen (GED-0301) showed promising results in patients with active Crohn’s disease in phase 1 and 2 phase trials, but further phase 3 study failed due to lack of clinical benefit (EudraCT 2009-012465-66, EudraCT 2011-002640-27, and NCT02596893).1046,1047,1048 Meanwhile, SMAD3 antisense oligonucleotide treatment was found to improve flexor tendon repair in mice and might have possible therapeutic applications in clinical practice.877
Moreover, a small-molecule SMAD3 inhibitor known as specific inhibitor of SMAD3 (SIS3) has shown pre-clinical therapeutic efficacy in wound healing,1049 cardiovascular diseases,569,1050,1051 nervous diseases,1052 renal diseases,1053,1054 skeletal diseases,1055 fibrotic diseases,1056,1057 inflammatory diseases,1039,1058 type 2 diabetes,1059,1060 and tumors,1061,1062 suggesting a novel approach that could be further tested to treat clinical patients.
Furthermore, several SMAD-binding peptide aptamers have been developed to selectively inhibit the binding between SMADs and their interacting factors.1063 An aptamer containing the SMAD-binding domain of transcription factor lymphoid enhancer-binding factor 1 (LEF1) can suppress tumor cell proliferation by inhibiting the interaction between SMAD4 and LEF/T cell-specific factor (TCF) to suppress MYC expression.1064 Other aptamers that bind specifically to R-SMADs through the SMAD-binding domain from SARA can impair the formation of functional SMAD oligomers to inhibit TGF-β-induced EMT.1065,1066 Moreover, aptamers that disrupt the interaction between SMAD and transcription coactivator yes-associated protein (YAP) have been designed for bone tumor therapy.1067
Conclusions and future perspectives
TGF-β signaling is so extensively and indispensably involved in a large number of biological processes that it has attracted great interest and attention over the past decades during which relevant knowledge has exploded in the fields of health, disease, and therapeutics. However, there are still some specific issues that have not been fully elucidated, while some previous knowledge is facing updates and challenges.
Studies on embryonic development and wound healing have revealed the isoform-specific roles of TGF-β which remain poorly aware in other fields of research, as studies on immune homeostasis, fibrotic diseases, and tumor development so far have focused on the most abundant TGF-β1 isoform in particular. Since all TGF-β isoforms are believed to signal through the same receptors and downstream pathways, the causes of the differences in biological effects between isotypes have not been fully understood. Moreover, since a natural TGF-β heterodimer containing one TGF-β1 monomer and one TGF-β2 monomer has long been discovered,12,1068 it would be very interesting to identify and characterize novel TGF-β heterodimers in the future. Furthermore, with the discovery and study of TGF-β superfamily which also includes polypeptides structurally similar to TGF-β such as nodal, myostatin, inhibins, activins, Müllerian-inhibiting substance (MIS), bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), researchers have realized that TGF-β can also signal through pathways ‘specific’ to other TGF-β superfamily members, for example, via receptors ALK1/2/3 and transcription factors SMAD1/5/8.1069,1070,1071,1072,1073 The significance of the signaling crosstalk within the TGF-β superfamily also warrants future exploration. Notably, Reblozyl (luspatercept or ACE-536), a ligand trap that contains the extracellular domain of human activin receptor type IIB (ActRIIB) to inhibit GDF11-mediated SMAD2/3 signaling has been approved by the US Federal Drug Agency (FDA) for the treatment of anemia in adult patients with β-thalassemia or with MDS.
As for TGF-β-targeting therapy, the efficacy and safety of treatment are always issues of concern. The current lack of systematic studies on the dural roles of TGF-β in wound healing, infectious diseases, and tumor development may hinder the development of related therapeutics. Given the extensive impacts of TGF-β on a lot of biological processes, the development of TGF-β isoform-specific therapies and SMAD-binding peptide aptamers is expected to cause less adverse effects through more precise targeting. Moreover, the identification of the applicable population for each therapeutic approach is also important for better efficacy and less toxicity. Serum and tissue levels of TGF-β have shown potential as predictors or indicators of the development,1074,1075,1076,1077 complication,1078,1079,1080 response,1081,1082,1083,1084 recurrence,1085,1086,1087 and outcomes1088,1089,1090 of various kinds of diseases, meanwhile, bioinformatic tools of TGF-β signaling-related gene expression signatures have also been developed for patient stratification.863,1091 But so far, TGF-β or related factors as clinical biomarkers still need further development and assessment.
To summarize, this review focuses on the multiple roles of TGF-β in health and disease while emphasizing the mechanisms of TGF-β production, activation, signaling, as well as corresponding therapeutic strategies. These understandings might be instructive for the basic and applied research of relevant topics in the future.
Data availability
Not applicable.
References
de Larco, J. E. & Todaro, G. J. Growth factors from murine sarcoma virus-transformed cells. Proc. Natl Acad. Sci. USA 75, 4001–4005 (1978).
Derynck, R. et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 316, 701–705 (1985).
Roberts, A. B., Anzano, M. A., Lamb, L. C., Smith, J. M. & Sporn, M. B. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc. Natl Acad. Sci. USA 78, 5339–5343 (1981).
Proper, J. A., Bjornson, C. L. & Moses, H. L. Mouse embryos contain polypeptide growth factor(s) capable of inducing a reversible neoplastic phenotype in nontransformed cells in culture. J. Cell Physiol. 110, 169–174 (1982).
Childs, C. B., Proper, J. A., Tucker, R. F. & Moses, H. L. Serum contains a platelet-derived transforming growth factor. Proc. Natl Acad. Sci. USA 79, 5312–5316 (1982).
Moses, H. L., Branum, E. L., Proper, J. A. & Robinson, R. A. Transforming growth factor production by chemically transformed cells. Cancer Res 41, 2842–2848 (1981).
Assoian, R. K., Komoriya, A., Meyers, C. A., Miller, D. M. & Sporn, M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J. Biol. Chem. 258, 7155–7160 (1983).
Roberts, A. B. et al. Purification and properties of a type beta transforming growth factor from bovine kidney. Biochemistry 22, 5692–5698 (1983).
Miyazono, K., Hellman, U., Wernstedt, C. & Heldin, C. H. Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J. Biol. Chem. 263, 6407–6415 (1988).
Wakefield, L. M., Smith, D. M., Flanders, K. C. & Sporn, M. B. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J. Biol. Chem. 263, 7646–7654 (1988).
Lawrence, D. A., Pircher, R. & Jullien, P. Conversion of a high molecular weight latent beta-TGF from chicken embryo fibroblasts into a low molecular weight active beta-TGF under acidic conditions. Biochem Biophys. Res Commun. 133, 1026–1034 (1985).
Cheifetz, S. et al. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell 48, 409–415 (1987).
ten Dijke, P., Hansen, P., Iwata, K. K., Pieler, C. & Foulkes, J. G. Identification of another member of the transforming growth factor type beta gene family. Proc. Natl Acad. Sci. USA 85, 4715–4719 (1988).
Derynck, R. et al. A new type of transforming growth factor-beta, TGF-beta 3. EMBO J. 7, 3737–3743 (1988).
Tucker, R. F., Shipley, G. D., Moses, H. L. & Holley, R. W. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science 226, 705–707 (1984).
Holley, R. W., Armour, R. & Baldwin, J. H. Density-dependent regulation of growth of BSC-1 cells in cell culture: growth inhibitors formed by the cells. Proc. Natl Acad. Sci. USA 75, 1864–1866 (1978).
Ignotz, R. A. & Massague, J. Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc. Natl Acad. Sci. USA 82, 8530–8534 (1985).
Seyedin, S. M., Thomas, T. C., Thompson, A. Y., Rosen, D. M. & Piez, K. A. Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc. Natl Acad. Sci. USA 82, 2267–2271 (1985).
Heine, U. et al. Role of transforming growth factor-beta in the development of the mouse embryo. J. Cell Biol. 105, 2861–2876 (1987).
Sporn, M. B. et al. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science 219, 1329–1331 (1983).
Rook, A. H. et al. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J. Immunol. 136, 3916–3920 (1986).
Kehrl, J. H. et al. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J. Immunol. 137, 3855–3860 (1986).
Border, W. A., Okuda, S., Languino, L. R., Sporn, M. B. & Ruoslahti, E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346, 371–374 (1990).
Connor, T. B. Jr. et al. Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye. J. Clin. Invest 83, 1661–1666 (1989).
Pierce, D. F. Jr. et al. Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc. Natl Acad. Sci. USA 92, 4254–4258 (1995).
Markowitz, S. et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).
Massague, J., Czech, M. P., Iwata, K., DeLarco, J. E. & Todaro, G. J. Affinity labeling of a transforming growth factor receptor that does not interact with epidermal growth factor. Proc. Natl Acad. Sci. USA 79, 6822–6826 (1982).
Frolik, C. A., Wakefield, L. M., Smith, D. M. & Sporn, M. B. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. J. Biol. Chem. 259, 10995–11000 (1984).
Massagué, J. & Like, B. Cellular receptors for type beta transforming growth factor. Ligand binding and affinity labeling in human and rodent cell lines. J. Biol. Chem. 260, 2636–2645 (1985).
Eppert, K. et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543–552 (1996).
Zhang, Y., Feng, X., We, R. & Derynck, R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383, 168–172 (1996).
Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).
Schlingensiepen, K. H. et al. Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. Cytokine Growth Factor Rev. 17, 129–139 (2006).
Fakhrai, H. et al. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther. 13, 1052–1060 (2006).
Nemunaitis, J. et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J. Clin. Oncol. 24, 4721–4730 (2006).
Trachtman, H. et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79, 1236–1243 (2011).
Rodon, J. et al. First-in-human dose study of the novel transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin. Cancer Res 21, 553–560 (2015).
Rodón, J. et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest N. Drugs 33, 357–370 (2015).
Strauss, J. et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin. Cancer Res 24, 1287–1295 (2018).
Dubois, C. M., Laprise, M. H., Blanchette, F., Gentry, L. E. & Leduc, R. Processing of transforming growth factor beta 1 precursor by human furin convertase. J. Biol. Chem. 270, 10618–10624 (1995).
Shi, M. et al. Latent TGF-beta structure and activation. Nature 474, 343–349 (2011).
Miyazono, K., Olofsson, A., Colosetti, P. & Heldin, C. H. A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J. 10, 1091–1101 (1991).
Lockhart-Cairns, M. P. et al. Latent TGFbeta complexes are transglutaminase cross-linked to fibrillin to facilitate TGFbeta activation. Matrix Biol. 107, 24–39 (2022).
Tran, D. Q. et al. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc. Natl Acad. Sci. USA 106, 13445–13450 (2009).
Qin, Y. et al. A Milieu Molecule for TGF-beta Required for Microglia Function in the Nervous System. Cell 174, 156–171.e116 (2018).
Annes, J. P., Rifkin, D. B. & Munger, J. S. The integrin alphaVbeta6 binds and activates latent TGFbeta3. FEBS Lett. 511, 65–68 (2002).
Breuss, J. M. et al. Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J. Cell Sci. 108, 2241–2251 (1995).
Mu, D. et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J. Cell Biol. 157, 493–507 (2002).
Kitamura, H. et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin alphavbeta8-mediated activation of TGF-beta. J. Clin. Invest 121, 2863–2875 (2011).
Kelly, A. et al. Human monocytes and macrophages regulate immune tolerance via integrin alphavbeta8-mediated TGFbeta activation. J. Exp. Med 215, 2725–2736 (2018).
Worthington, J. J., Czajkowska, B. I., Melton, A. C. & Travis, M. A. Intestinal dendritic cells specialize to activate transforming growth factor-beta and induce Foxp3+ regulatory T cells via integrin alphavbeta8. Gastroenterology 141, 1802–1812 (2011).
Laine, A. et al. Regulatory T cells promote cancer immune-escape through integrin alphavbeta8-mediated TGF-beta activation. Nat. Commun. 12, 6228 (2021).
Takasaka, N. et al. Integrin alphavbeta8-expressing tumor cells evade host immunity by regulating TGF-beta activation in immune cells. JCI Insight 3, e122591 (2018).
Yang, Z. et al. Absence of integrin-mediated TGFbeta1 activation in vivo recapitulates the phenotype of TGFbeta1-null mice. J. Cell Biol. 176, 787–793 (2007).
Aluwihare, P. et al. Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J. Cell Sci. 122, 227–232 (2009).
Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-beta. Nature 542, 55–59 (2017).
Wang, R. et al. GARP regulates the bioavailability and activation of TGFbeta. Mol. Biol. Cell 23, 1129–1139 (2012).
Edwards, J. P. et al. Regulation of the expression of GARP/latent TGF-beta1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation. J. Immunol. 190, 5506–5515 (2013).
Stockis, J. et al. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin alphaVbeta8. Proc. Natl Acad. Sci. USA 114, E10161–E10168 (2017).
Campbell, M. G. et al. Cryo-EM Reveals Integrin-Mediated TGF-beta Activation without Release from Latent TGF-beta. Cell 180, 490–501.e416 (2020).
Lawrence, D. A., Pircher, R., Krycève-Martinerie, C. & Jullien, P. Normal embryo fibroblasts release transforming growth factors in a latent form. J. Cell Physiol. 121, 184–188 (1984).
Brown, P. D., Wakefield, L. M., Levinson, A. D. & Sporn, M. B. Physicochemical activation of recombinant latent transforming growth factor-beta’s 1, 2, and 3. Growth Factors 3, 35–43 (1990).
Jullien, P., Berg, T. M. & Lawrence, D. A. Acidic cellular environments: activation of latent TGF-beta and sensitization of cellular responses to TGF-beta and EGF. Int J. Cancer 43, 886–891 (1989).
Silver, I. A., Murrills, R. J. & Etherington, D. J. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp. Cell Res 175, 266–276 (1988).
Kottmann, R. M. et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. Am. J. Respir. Crit. Care Med 186, 740–751 (2012).
Jobling, M. F. et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat. Res 166, 839–848 (2006).
Hayashi, H., Sakai, K., Baba, H. & Sakai, T. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice. Hepatology 55, 1562–1573 (2012).
Wang, H. & Kochevar, I. E. Involvement of UVB-induced reactive oxygen species in TGF-beta biosynthesis and activation in keratinocytes. Free Radic. Biol. Med 38, 890–897 (2005).
Pociask, D. A., Sime, P. J. & Brody, A. R. Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest 84, 1013–1023 (2004).
Sullivan, D. E., Ferris, M., Pociask, D. & Brody, A. R. The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo. J. Immunotoxicol. 5, 145–149 (2008).
Barcellos-Hoff, M. H. & Dix, T. A. Redox-mediated activation of latent transforming growth factor-beta 1. Mol. Endocrinol. 10, 1077–1083 (1996).
Ning, W. et al. Effect of high glucose supplementation on pulmonary fibrosis involving reactive oxygen species and TGF-beta. Front Nutr. 9, 998662 (2022).
Zhang, D. et al. High Glucose Intake Exacerbates Autoimmunity through Reactive-Oxygen-Species-Mediated TGF-beta Cytokine Activation. Immunity 51, 671–681.e675 (2019).
Chen, W., Frank, M. E., Jin, W. & Wahl, S. M. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14, 715–725 (2001).
Amarnath, S., Dong, L., Li, J., Wu, Y. & Chen, W. Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells. Retrovirology 4, 57 (2007).
Sweetwyne, M. T. & Murphy-Ullrich, J. E. Thrombospondin1 in tissue repair and fibrosis: TGF-beta-dependent and independent mechanisms. Matrix Biol. 31, 178–186 (2012).
Murphy-Ullrich, J. E. & Suto, M. J. Thrombospondin-1 regulation of latent TGF-beta activation: A therapeutic target for fibrotic disease. Matrix Biol. 68-69, 28–43 (2018).
Murphy-Ullrich, J. E., Schultz-Cherry, S. & Hook, M. Transforming growth factor-beta complexes with thrombospondin. Mol. Biol. Cell 3, 181–188 (1992).
Yung, S. et al. Elevated glucose induction of thrombospondin-1 up-regulates fibronectin synthesis in proximal renal tubular epithelial cells through TGF-beta1 dependent and TGF-beta1 independent pathways. Nephrol. Dial. Transpl. 21, 1504–1513 (2006).
Naito, T. et al. Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK: a mechanism for activation of latent TGF-beta1. Am. J. Physiol. Ren. Physiol. 286, F278–F287 (2004).
Kumar, R. et al. Interstitial macrophage-derived thrombospondin-1 contributes to hypoxia-induced pulmonary hypertension. Cardiovasc Res 116, 2021–2030 (2020).
Matsuba, M., Hutcheon, A. E. & Zieske, J. D. Localization of thrombospondin-1 and myofibroblasts during corneal wound repair. Exp. Eye Res 93, 534–540 (2011).
Doyen, V. et al. Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J. Exp. Med 198, 1277–1283 (2003).
McMaken, S. et al. Thrombospondin-1 contributes to mortality in murine sepsis through effects on innate immunity. PLoS One 6, e19654 (2011).
Presser, L. D., Haskett, A. & Waris, G. Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-beta1: role of TGF-beta1 in HCV replication. Virology 412, 284–296 (2011).
Kumar, R. et al. TGF-beta activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension. Nat. Commun. 8, 15494 (2017).
Zhou, Y., Poczatek, M. H., Berecek, K. H. & Murphy-Ullrich, J. E. Thrombospondin 1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions. Biochem Biophys. Res Commun. 339, 633–641 (2006).
Atanasova, V. S. et al. Thrombospondin-1 Is a Major Activator of TGF-beta Signaling in Recessive Dystrophic Epidermolysis Bullosa Fibroblasts. J. Invest Dermatol 139, 1497–1505.e1495 (2019).
Presser, L. D., Haskett, A. & Waris, G. Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-β1: role of TGF-β1 in HCV replication. Virology 412, 284–296 (2011).
Matsumura, K. et al. Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-beta signal activation in pancreatic ductal adenocarcinoma. Transl. Oncol. 26, 101533 (2022).
Jenkins, G. The role of proteases in transforming growth factor-beta activation. Int J. Biochem. Cell Biol. 40, 1068–1078 (2008).
Lu, L. et al. Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-beta is critical for immune homeostasis following acute liver injury. J. Mol. Cell Biol. 5, 369–379 (2013).
Bai, P. et al. Macrophage-Derived Legumain Promotes Pulmonary Hypertension by Activating the MMP (Matrix Metalloproteinase)-2/TGF (Transforming Growth Factor)-β1 Signaling. Arterioscler Thromb. Vasc. Biol. 39, e130–e145 (2019).
Feng, W. et al. Matrix metalloproteinase-9 regulates afferent arteriolar remodeling and function in hypertension-induced kidney disease. Kidney Int 104, 740–753 (2023).
Espindola, M. S. et al. Differential Responses to Targeting Matrix Metalloproteinase 9 in Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med 203, 458–470 (2021).
Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).
Yehualaeshet, T. et al. Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am. J. Pathol. 155, 841–851 (1999).
Nunes, I., Shapiro, R. L. & Rifkin, D. B. Characterization of latent TGF-beta activation by murine peritoneal macrophages. J. Immunol. 155, 1450–1459 (1995).
Kojima, S. & Rifkin, D. B. Mechanism of retinoid-induced activation of latent transforming growth factor-beta in bovine endothelial cells. J. Cell Physiol. 155, 323–332 (1993).
Sato, Y. & Rifkin, D. B. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J. Cell Biol. 109, 309–315 (1989).
Sankar, S., Mahooti-Brooks, N., Centrella, M., McCarthy, T. L. & Madri, J. A. Expression of transforming growth factor type III receptor in vascular endothelial cells increases their responsiveness to transforming growth factor beta 2. J. Biol. Chem. 270, 13567–13572 (1995).
Cheifetz, S. et al. Distinct transforming growth factor-beta (TGF-beta) receptor subsets as determinants of cellular responsiveness to three TGF-beta isoforms. J. Biol. Chem. 265, 20533–20538 (1990).
Wang, X. F. et al. Expression cloning and characterization of the TGF-beta type III receptor. Cell 67, 797–805 (1991).
Lopez-Casillas, F. et al. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system. Cell 67, 785–795 (1991).
Lopez-Casillas, F., Wrana, J. L. & Massague, J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73, 1435–1444 (1993).
Esparza-Lopez, J. et al. Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions for transforming growth factor-beta and inhibin A. J. Biol. Chem. 276, 14588–14596 (2001).
Madamanchi, A., Ingle, M., Hinck, A. P. & Umulis, D. M. Computational modeling of TGF-β2:TβRI:TβRII receptor complex assembly as mediated by the TGF-β coreceptor betaglycan. Biophys. J. 122, 1342–1354 (2023).
Zhang, W. et al. Single-molecule imaging reveals transforming growth factor-beta-induced type II receptor dimerization. Proc. Natl Acad. Sci. USA 106, 15679–15683 (2009).
Gilboa, L., Wells, R. G., Lodish, H. F. & Henis, Y. I. Oligomeric structure of type I and type II transforming growth factor beta receptors: homodimers form in the ER and persist at the plasma membrane. J. Cell Biol. 140, 767–777 (1998).
Chen, R. H. & Derynck, R. Homomeric interactions between type II transforming growth factor-beta receptors. J. Biol. Chem. 269, 22868–22874 (1994).
Groppe, J. et al. Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29, 157–168 (2008).
Wrana, J. L. et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003–1014 (1992).
Huse, M. et al. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol. Cell 8, 671–682 (2001).
Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L. & Wrana, J. L. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95, 779–791 (1998).
Wu, J. W. et al. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol. Cell 8, 1277–1289 (2001).
Kawabata, M., Inoue, H., Hanyu, A., Imamura, T. & Miyazono, K. Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors. Embo j. 17, 4056–4065 (1998).
Chacko, B. M. et al. The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization. Nat. Struct. Biol. 8, 248–253 (2001).
Lucarelli, P. et al. Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression. Cell Syst. 6, 75–89.e11 (2018).
Inman, G. J. & Hill, C. S. Stoichiometry of active smad-transcription factor complexes on DNA. J. Biol. Chem. 277, 51008–51016 (2002).
Shi, Y. et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94, 585–594 (1998).
Martin-Malpartida, P. et al. Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. Nat. Commun. 8, 2070 (2017).
Zawel, L. et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611–617 (1998).
Liu, Z. et al. Global identification of SMAD2 target genes reveals a role for multiple co-regulatory factors in zebrafish early gastrulas. J. Biol. Chem. 286, 28520–28532 (2011).
Koinuma, D. et al. Promoter-wide analysis of Smad4 binding sites in human epithelial cells. Cancer Sci. 100, 2133–2142 (2009).
Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147, 565–576 (2011).
Afrakhte, M. et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochem Biophys. Res Commun. 249, 505–511 (1998).
Denissova, N. G., Pouponnot, C., Long, J., He, D. & Liu, F. Transforming growth factor beta -inducible independent binding of SMAD to the Smad7 promoter. Proc. Natl Acad. Sci. USA 97, 6397–6402 (2000).
Imamura, T. et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389, 622–626 (1997).
Kamiya, Y., Miyazono, K. & Miyazawa, K. Smad7 inhibits transforming growth factor-beta family type i receptors through two distinct modes of interaction. J. Biol. Chem. 285, 30804–30813 (2010).
Hanyu, A. et al. The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling. J. Cell Biol. 155, 1017–1027 (2001).
Suzuki, C. et al. Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J. Biol. Chem. 277, 39919–39925 (2002).
Kavsak, P. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol. Cell 6, 1365–1375 (2000).
Yan, X. et al. Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling. J. Biol. Chem. 291, 382–392 (2016).
Kuratomi, G. et al. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 386, 461–470 (2005).
Morén, A., Imamura, T., Miyazono, K., Heldin, C. H. & Moustakas, A. Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J. Biol. Chem. 280, 22115–22123 (2005).
Shi, W. et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J. Cell Biol. 164, 291–300 (2004).
Zhang, S. et al. Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation. Mol. Cell Biol. 27, 4488–4499 (2007).
Ross, S. et al. Smads orchestrate specific histone modifications and chromatin remodeling to activate transcription. Embo j. 25, 4490–4502 (2006).
Feng, X. H., Zhang, Y., Wu, R. Y. & Derynck, R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 12, 2153–2163 (1998).
Itoh, S., Ericsson, J., Nishikawa, J., Heldin, C. H. & ten Dijke, P. The transcriptional co-activator P/CAF potentiates TGF-beta/Smad signaling. Nucleic Acids Res 28, 4291–4298 (2000).
Kahata, K. et al. Regulation of transforming growth factor-beta and bone morphogenetic protein signalling by transcriptional coactivator GCN5. Genes Cells 9, 143–151 (2004).
Yahata, T. et al. The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J. Biol. Chem. 275, 8825–8834 (2000).
Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. Embo j. 22, 2443–2452 (2003).
Postigo, A. A., Depp, J. L., Taylor, J. J. & Kroll, K. L. Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. Embo j. 22, 2453–2462 (2003).
Shuttleworth, V. G. et al. The methyltransferase SET9 regulates TGFB1 activation of renal fibroblasts via interaction with SMAD3. J. Cell Sci. 131, jcs207761 (2018).
Kang, J. S., Alliston, T., Delston, R. & Derynck, R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. Embo j. 24, 2543–2555 (2005).
Wotton, D., Lo, R. S., Lee, S. & Massagué, J. A Smad transcriptional corepressor. Cell 97, 29–39 (1999).
Alliston, T. et al. Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. J. Biol. Chem. 280, 24227–24237 (2005).
Izutsu, K. et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood 97, 2815–2822 (2001).
Luo, K. et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev. 13, 2196–2206 (1999).
Akiyoshi, S. et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J. Biol. Chem. 274, 35269–35277 (1999).
Sun, Y. et al. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol. Cell 4, 499–509 (1999).
Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q. & Luo, K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286, 771–774 (1999).
Feng, X. H., Liang, Y. Y., Liang, M., Zhai, W. & Lin, X. Direct Interaction of c-Myc with Smad2 and Smad3 to Inhibit TGF-β-Mediated Induction of the CDK Inhibitor p15(Ink4B). Mol. Cell 63, 1089 (2016).
Kim, R. H. et al. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev. 14, 1605–1616 (2000).
Verschueren, K. et al. SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5’-CACCT sequences in candidate target genes. J. Biol. Chem. 274, 20489–20498 (1999).
Wakabayashi, Y. et al. Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-Smad pathway. J. Biol. Chem. 286, 35456–35465 (2011).
Du, D. et al. Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition. EMBO Rep. 19, 135–155 (2018).
Brown, J. D., DiChiara, M. R., Anderson, K. R., Gimbrone, M. A. Jr. & Topper, J. N. MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J. Biol. Chem. 274, 8797–8805 (1999).
Kamaraju, A. K. & Roberts, A. B. Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J. Biol. Chem. 280, 1024–1036 (2005).
Mori, S. et al. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 23, 7416–7429 (2004).
Lehmann, K. et al. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 14, 2610–2622 (2000).
Funaba, M., Zimmerman, C. M. & Mathews, L. S. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J. Biol. Chem. 277, 41361–41368 (2002).
Roelen, B. A. et al. Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-beta-induced nuclear accumulation. Am. J. Physiol. Cell Physiol. 285, C823–C830 (2003).
Guo, X. et al. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes Dev. 22, 106–120 (2008).
Millet, C. et al. A negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204. J. Biol. Chem. 284, 19808–19816 (2009).
Wang, G., Matsuura, I., He, D. & Liu, F. Transforming growth factor-{beta}-inducible phosphorylation of Smad3. J. Biol. Chem. 284, 9663–9673 (2009).
Wicks, S. J., Lui, S., Abdel-Wahab, N., Mason, R. M. & Chantry, A. Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol. Cell Biol. 20, 8103–8111 (2000).
Yakymovych, I., Ten Dijke, P., Heldin, C. H. & Souchelnytskyi, S. Regulation of Smad signaling by protein kinase C. Faseb j. 15, 553–555 (2001).
Saura, M. et al. Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells. Circ. Res 97, 1115–1123 (2005).
Alarcón, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139, 757–769 (2009).
Matsuura, I. et al. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430, 226–231 (2004).
Sapkota, G. et al. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J. Biol. Chem. 281, 40412–40419 (2006).
Wrighton, K. H. et al. Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling. J. Biol. Chem. 281, 38365–38375 (2006).
Lin, X. et al. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 125, 915–928 (2006).
Yu, J. et al. MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes. J. Biol. Chem. 285, 8454–8462 (2010).
Heikkinen, P. T. et al. Hypoxia-activated Smad3-specific dephosphorylation by PP2A. J. Biol. Chem. 285, 3740–3749 (2010).
Lin, X., Liang, M. & Feng, X. H. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J. Biol. Chem. 275, 36818–36822 (2000).
Zhang, Y., Chang, C., Gehling, D. J., Hemmati-Brivanlou, A. & Derynck, R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 98, 974–979 (2001).
Tang, L. Y. et al. Ablation of Smurf2 reveals an inhibition in TGF-β signalling through multiple mono-ubiquitination of Smad3. Embo j. 30, 4777–4789 (2011).
Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol. Cell 36, 457–468 (2009).
Komuro, A. et al. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23, 6914–6923 (2004).
Seo, S. R. et al. The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. Embo j. 23, 3780–3792 (2004).
Soond, S. M. & Chantry, A. Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT. Oncogene 30, 2451–2462 (2011).
Mavrakis, K. J. et al. Arkadia enhances Nodal/TGF-beta signaling by coupling phospho-Smad2/3 activity and turnover. PLoS Biol. 5, e67 (2007).
Xin, H. et al. CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J. Biol. Chem. 280, 20842–20850 (2005).
Bai, Y., Yang, C., Hu, K., Elly, C. & Liu, Y. C. Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation. Mol. Cell 15, 825–831 (2004).
Fukuchi, M. et al. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol. Biol. Cell 12, 1431–1443 (2001).
Wan, M. et al. Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J. Biol. Chem. 279, 14484–14487 (2004).
Tang, L. Y. & Zhang, Y. E. Non-degradative ubiquitination in Smad-dependent TGF-β signaling. Cell Biosci. 1, 43 (2011).
Aragón, E. et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 25, 1275–1288 (2011).
Lee, M. K. et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. Embo j. 26, 3957–3967 (2007).
Lavoie, H., Gagnon, J. & Therrien, M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat. Rev. Mol. Cell Biol. 21, 607–632 (2020).
Lu, N. & Malemud, C. J. Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone Cell Receptor-Mediated Gene Expression. Int J. Mol. Sci. 20, 3792 (2019).
Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).
Papadimitriou, E., Kardassis, D., Moustakas, A. & Stournaras, C. TGFβ-induced early activation of the small GTPase RhoA is Smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2. Cell Physiol. Biochem 28, 229–238 (2011).
Lu, X. et al. Effect of RhoC on the epithelial-mesenchymal transition process induced by TGF-β1 in lung adenocarcinoma cells. Oncol. Rep. 36, 3105–3112 (2016).
Bhowmick, N. A. et al. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27–36 (2001).
Shen, X. et al. The activity of guanine exchange factor NET1 is essential for transforming growth factor-beta-mediated stress fiber formation. J. Biol. Chem. 276, 15362–15368 (2001).
Papadimitriou, E. et al. Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-β and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 31, 2862–2875 (2012).
Vardouli, L., Moustakas, A. & Stournaras, C. LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-beta. J. Biol. Chem. 280, 11448–11457 (2005).
Lee, J., Ko, M. & Joo, C. K. Rho plays a key role in TGF-beta1-induced cytoskeletal rearrangement in human retinal pigment epithelium. J. Cell Physiol. 216, 520–526 (2008).
Sousa-Squiavinato, A. C. M., Rocha, M. R., Barcellos-de-Souza, P., de Souza, W. F. & Morgado-Diaz, J. A. Cofilin-1 signaling mediates epithelial-mesenchymal transition by promoting actin cytoskeleton reorganization and cell-cell adhesion regulation in colorectal cancer cells. Biochim Biophys. Acta Mol. Cell Res 1866, 418–429 (2019).
Wei, Y. H., Liao, S. L., Wang, S. H., Wang, C. C. & Yang, C. H. Simvastatin and ROCK Inhibitor Y-27632 Inhibit Myofibroblast Differentiation of Graves’ Ophthalmopathy-Derived Orbital Fibroblasts via RhoA-Mediated ERK and p38 Signaling Pathways. Front Endocrinol. (Lausanne) 11, 607968 (2020).
Matoba, K. et al. Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy. Int J. Mol. Sci. 18, 1795 (2017).
Edlund, S., Landström, M., Heldin, C. H. & Aspenström, P. Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol. Biol. Cell 13, 902–914 (2002).
Jaffe, A. B. & Hall, A. Rho GTPases: biochemistry and biology. Annu Rev. Cell Dev. Biol. 21, 247–269 (2005).
Nomikou, E., Livitsanou, M., Stournaras, C. & Kardassis, D. Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases. Cell Mol. Life Sci. 75, 2111–2124 (2018).
Zhang, L. et al. TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis. Mol. Cell 51, 559–572 (2013).
Sorrentino, A. et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199–1207 (2008).
Yamashita, M. et al. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol. Cell 31, 918–924 (2008).
Engel, M. E., McDonnell, M. A., Law, B. K. & Moses, H. L. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J. Biol. Chem. 274, 37413–37420 (1999).
Atfi, A., Djelloul, S., Chastre, E., Davis, R. & Gespach, C. Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling. J. Biol. Chem. 272, 1429–1432 (1997).
Minden, A., Lin, A., Claret, F. X., Abo, A. & Karin, M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81, 1147–1157 (1995).
Coso, O. A. et al. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81, 1137–1146 (1995).
Mazars, A. et al. Differential roles of JNK and Smad2 signaling pathways in the inhibition of c-Myc-induced cell death by TGF-beta. Oncogene 19, 1277–1287 (2000).
Hocevar, B. A., Brown, T. L. & Howe, P. H. TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. Embo j. 18, 1345–1356 (1999).
Zeke, A., Misheva, M., Reményi, A. & Bogoyevitch, M. A. JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol. Biol. Rev. 80, 793–835 (2016).
Yu, L., Hébert, M. C. & Zhang, Y. E. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. Embo j. 21, 3749–3759 (2002).
Canovas, B. & Nebreda, A. R. Diversity and versatility of p38 kinase signalling in health and disease. Nat. Rev. Mol. Cell Biol. 22, 346–366 (2021).
Hamidi, A. et al. Polyubiquitination of transforming growth factor β (TGFβ)-associated kinase 1 mediates nuclear factor-κB activation in response to different inflammatory stimuli. J. Biol. Chem. 287, 123–133 (2012).
Kim, H. J., Kim, J. G., Moon, M. Y., Park, S. H. & Park, J. B. IκB kinase γ/nuclear factor-κB-essential modulator (IKKγ/NEMO) facilitates RhoA GTPase activation, which, in turn, activates Rho-associated KINASE (ROCK) to phosphorylate IKKβ in response to transforming growth factor (TGF)-β1. J. Biol. Chem. 289, 1429–1440 (2014).
Rodriguez, P. L., Sahay, S., Olabisi, O. O. & Whitehead, I. P. ROCK I-mediated activation of NF-kappaB by RhoB. Cell Signal 19, 2361–2369 (2007).
Zhu, X. et al. TGF-beta1-induced PI3K/Akt/NF-kappaB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts. J. Biochem 149, 405–414 (2011).
Capece, D. et al. NF-κB: blending metabolism, immunity, and inflammation. Trends Immunol. 43, 757–775 (2022).
Zinatizadeh, M. R. et al. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 8, 287–297 (2021).
Liu, D., Zhong, Z. & Karin, M. NF-κB: A Double-Edged Sword Controlling Inflammation. Biomedicines 10, 1250 (2022).
Yi, J. Y., Shin, I. & Arteaga, C. L. Type I transforming growth factor beta receptor binds to and activates phosphatidylinositol 3-kinase. J. Biol. Chem. 280, 10870–10876 (2005).
Hamidi, A. et al. TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α. Sci. Signal 10, eaal4186 (2017).
Bakin, A. V., Tomlinson, A. K., Bhowmick, N. A., Moses, H. L. & Arteaga, C. L. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem. 275, 36803–36810 (2000).
Lamouille, S. & Derynck, R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol. 178, 437–451 (2007).
Lamouille, S., Connolly, E., Smyth, J. W., Akhurst, R. J. & Derynck, R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J. Cell Sci. 125, 1259–1273 (2012).
Chen, X. H. et al. The TGF-β-induced up-regulation of NKG2DLs requires AKT/GSK-3β-mediated stabilization of SP1. J. Cell Mol. Med 21, 860–870 (2017).
Kato, M. et al. Role of the Akt/FoxO3a pathway in TGF-beta1-mediated mesangial cell dysfunction: a novel mechanism related to diabetic kidney disease. J. Am. Soc. Nephrol. 17, 3325–3335 (2006).
Franke, T. F. PI3K/Akt: getting it right matters. Oncogene 27, 6473–6488 (2008).
Liu, Y. et al. Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. J. Biol. Chem. 288, 30708–30719 (2013).
Tang, L. Y. et al. Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway. J. Biol. Chem. 292, 4302–4312 (2017).
Dees, C. et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 64, 3006–3015 (2012).
Philips, R. L. et al. The JAK-STAT pathway at 30: Much learned, much more to do. Cell 185, 3857–3876 (2022).
Lehnert, S. A. & Akhurst, R. J. Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development 104, 263–273 (1988).
Pelton, R. W., Nomura, S., Moses, H. L. & Hogan, B. L. Expression of transforming growth factor beta 2 RNA during murine embryogenesis. Development 106, 759–767 (1989).
Pelton, R. W., Dickinson, M. E., Moses, H. L. & Hogan, B. L. In situ hybridization analysis of TGF beta 3 RNA expression during mouse development: comparative studies with TGF beta 1 and beta 2. Development 110, 609–620 (1990).
Millan, F. A., Denhez, F., Kondaiah, P. & Akhurst, R. J. Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. Development 111, 131–143 (1991).
Pelton, R. W., Saxena, B., Jones, M., Moses, H. L. & Gold, L. I. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J. Cell Biol. 115, 1091–1105 (1991).
Rosa, F. et al. Mesoderm induction in amphibians: the role of TGF-beta 2-like factors. Science 239, 783–785 (1988).
Kimelman, D. & Kirschner, M. Synergistic induction of mesoderm by FGF and TGF-beta and the identification of an mRNA coding for FGF in the early Xenopus embryo. Cell 51, 869–877 (1987).
Bai, H., Xie, Y. L., Gao, Y. X., Cheng, T. & Wang, Z. Z. The balance of positive and negative effects of TGF-β signaling regulates the development of hematopoietic and endothelial progenitors in human pluripotent stem cells. Stem Cells Dev. 22, 2765–2776 (2013).
Zhang, C. Y. et al. Transforming growth factor-β1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis. Leukemia 32, 479–491 (2018).
Challen, G. A., Boles, N. C., Chambers, S. M. & Goodell, M. A. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell 6, 265–278 (2010).
Xie, Y. et al. Cooperative Effect of Erythropoietin and TGF-β Inhibition on Erythroid Development in Human Pluripotent Stem Cells. J. Cell Biochem 116, 2735–2743 (2015).
Ng, F. et al. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood 112, 295–307 (2008).
Jian, H. et al. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 20, 666–674 (2006).
Alliston, T., Choy, L., Ducy, P., Karsenty, G. & Derynck, R. TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. Embo j. 20, 2254–2272 (2001).
Liu, D., Black, B. L. & Derynck, R. TGF-beta inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3. Genes Dev. 15, 2950–2966 (2001).
Massagué, J., Cheifetz, S., Endo, T. & Nadal-Ginard, B. Type beta transforming growth factor is an inhibitor of myogenic differentiation. Proc. Natl Acad. Sci. USA 83, 8206–8210 (1986).
Florini, J. R. et al. Transforming growth factor-beta. A very potent inhibitor of myoblast differentiation, identical to the differentiation inhibitor secreted by Buffalo rat liver cells. J. Biol. Chem. 261, 16509–16513 (1986).
Zhu, S., Goldschmidt-Clermont, P. J. & Dong, C. Transforming growth factor-beta-induced inhibition of myogenesis is mediated through Smad pathway and is modulated by microtubule dynamic stability. Circ. Res 94, 617–625 (2004).
Choy, L. & Derynck, R. Transforming growth factor-beta inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function. J. Biol. Chem. 278, 9609–9619 (2003).
Choy, L., Skillington, J. & Derynck, R. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. J. Cell Biol. 149, 667–682 (2000).
Kurpinski, K. et al. Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells. Stem Cells 28, 734–742 (2010).
Seyedin, S. M. et al. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J. Biol. Chem. 261, 5693–5695 (1986).
Leonard, C. M. et al. Role of transforming growth factor-beta in chondrogenic pattern formation in the embryonic limb: stimulation of mesenchymal condensation and fibronectin gene expression by exogenenous TGF-beta and evidence for endogenous TGF-beta-like activity. Dev. Biol. 145, 99–109 (1991).
Reiss, M. & Sartorelli, A. C. Regulation of growth and differentiation of human keratinocytes by type beta transforming growth factor and epidermal growth factor. Cancer Res 47, 6705–6709 (1987).
Masui, T. et al. Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc. Natl Acad. Sci. USA 83, 2438–2442 (1986).
Yu, X. et al. The Cytokine TGF-β Promotes the Development and Homeostasis of Alveolar Macrophages. Immunity 47, 903–912.e904 (2017).
Clark, A. T., Young, R. J. & Bertram, J. F. In vitro studies on the roles of transforming growth factor-beta 1 in rat metanephric development. Kidney Int 59, 1641–1653 (2001).
Sanvito, F. et al. TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120, 3451–3462 (1994).
Böttinger, E. P. et al. Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. Embo j. 16, 2621–2633 (1997).
Huojia, M. et al. TGF-beta3 induces ectopic mineralization in fetal mouse dental pulp during tooth germ development. Dev. Growth Differ. 47, 141–152 (2005).
Yi, J. J., Barnes, A. P., Hand, R., Polleux, F. & Ehlers, M. D. TGF-beta signaling specifies axons during brain development. Cell 142, 144–157 (2010).
Stipursky, J. & Gomes, F. C. TGF-beta1/SMAD signaling induces astrocyte fate commitment in vitro: implications for radial glia development. Glia 55, 1023–1033 (2007).
Farkas, L. M., Dünker, N., Roussa, E., Unsicker, K. & Krieglstein, K. Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J. Neurosci. 23, 5178–5186 (2003).
Chleilat, E. et al. TGF-β Signaling Regulates Development of Midbrain Dopaminergic and Hindbrain Serotonergic Neuron Subgroups. Neuroscience 381, 124–137 (2018).
Araujo, A. P. et al. Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation. Front Cell Neurosci. 10, 104 (2016).
Morris, A. D., Lewis, G. M. & Kucenas, S. Perineurial Glial Plasticity and the Role of TGF-β in the Development of the Blood-Nerve Barrier. J. Neurosci. 37, 4790–4807 (2017).
de Sampaio e Spohr, T. C., Martinez, R., da Silva, E. F., Neto, V. M. & Gomes, F. C. Neuro-glia interaction effects on GFAP gene: a novel role for transforming growth factor-beta1. Eur. J. Neurosci. 16, 2059–2069 (2002).
Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994).
Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).
Jalali, A., Zhu, X., Liu, C. & Nawshad, A. Induction of palate epithelial mesenchymal transition by transforming growth factor β3 signaling. Dev. Growth Differ. 54, 633–648 (2012).
Nawshad, A. & Hay, E. D. TGFbeta3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J. Cell Biol. 163, 1291–1301 (2003).
Pelton, R. W., Hogan, B. L., Miller, D. A. & Moses, H. L. Differential expression of genes encoding TGFs beta 1, beta 2, and beta 3 during murine palate formation. Dev. Biol. 141, 456–460 (1990).
Fitzpatrick, D. R., Denhez, F., Kondaiah, P. & Akhurst, R. J. Differential expression of TGF beta isoforms in murine palatogenesis. Development 109, 585–595 (1990).
Brunet, C. L., Sharpe, P. M. & Ferguson, M. W. Inhibition of TGF-beta 3 (but not TGF-beta 1 or TGF-beta 2) activity prevents normal mouse embryonic palate fusion. Int J. Dev. Biol. 39, 345–355 (1995).
Sabbineni, H., Verma, A. & Somanath, P. R. Isoform-specific effects of transforming growth factor beta on endothelial-to-mesenchymal transition. J. Cell Physiol. 233, 8418–8428 (2018).
Molin, D. G. et al. Expression patterns of Tgfbeta1-3 associate with myocardialisation of the outflow tract and the development of the epicardium and the fibrous heart skeleton. Dev. Dyn. 227, 431–444 (2003).
Dickson, M. C., Slager, H. G., Duffie, E., Mummery, C. L. & Akhurst, R. J. RNA and protein localisations of TGF beta 2 in the early mouse embryo suggest an involvement in cardiac development. Development 117, 625–639 (1993).
Akhurst, R. J., Lehnert, S. A., Faissner, A. & Duffie, E. TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis. Development 108, 645–656 (1990).
Camenisch, T. D. et al. Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev. Biol. 248, 170–181 (2002).
Potts, J. D. & Runyan, R. B. Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta. Dev. Biol. 134, 392–401 (1989).
Azhar, M. et al. Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development. Dev. Dyn. 238, 431–442 (2009).
Nakajima, Y., Yamagishi, T., Nakamura, H., Markwald, R. R. & Krug, E. L. An autocrine function for transforming growth factor (TGF)-beta3 in the transformation of atrioventricular canal endocardium into mesenchyme during chick heart development. Dev. Biol. 194, 99–113 (1998).
Compton, L. A., Potash, D. A., Mundell, N. A. & Barnett, J. V. Transforming growth factor-beta induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells. Dev. Dyn. 235, 82–93 (2006).
Austin, A. F., Compton, L. A., Love, J. D., Brown, C. B. & Barnett, J. V. Primary and immortalized mouse epicardial cells undergo differentiation in response to TGFbeta. Dev. Dyn. 237, 366–376 (2008).
Liu, M. et al. Transforming Growth Factor-induced Protein Promotes NF-κB-mediated Angiogenesis during Postnatal Lung Development. Am. J. Respir. Cell Mol. Biol. 64, 318–330 (2021).
Ahmed, S., Liu, C. C. & Nawshad, A. Mechanisms of palatal epithelial seam disintegration by transforming growth factor (TGF) beta3. Dev. Biol. 309, 193–207 (2007).
Dunker, N., Schmitt, K. & Krieglstein, K. TGF-beta is required for programmed cell death in interdigital webs of the developing mouse limb. Mech. Dev. 113, 111–120 (2002).
Krieglstein, K. et al. Reduction of endogenous transforming growth factors beta prevents ontogenetic neuron death. Nat. Neurosci. 3, 1085–1090 (2000).
Dunker, N., Schuster, N. & Krieglstein, K. TGF-beta modulates programmed cell death in the retina of the developing chick embryo. Development 128, 1933–1942 (2001).
Schuster, N., Dunker, N. & Krieglstein, K. Transforming growth factor-beta induced cell death in the developing chick retina is mediated via activation of c-jun N-terminal kinase and downregulation of the anti-apoptotic protein Bcl-X(L). Neurosci. Lett. 330, 239–242 (2002).
Braunger, B. M. et al. TGF-β signaling protects retinal neurons from programmed cell death during the development of the mammalian eye. J. Neurosci. 33, 14246–14258 (2013).
Ruiz-Canada, C., Bernabe-Garcia, A., Liarte, S., Rodriguez-Valiente, M. & Nicolas, F. J. Chronic Wound Healing by Amniotic Membrane: TGF-beta and EGF Signaling Modulation in Re-epithelialization. Front Bioeng. Biotechnol. 9, 689328 (2021).
McMullen, H. et al. Spatial and temporal expression of transforming growth factor-beta isoforms during ovine excisional and incisional wound repair. Wound Repair Regen. 3, 141–156 (1995).
Gold, L. I., Sung, J. J., Siebert, J. W. & Longaker, M. T. Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair. Am. J. Pathol. 150, 209–222 (1997).
Mustoe, T. A. et al. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science 237, 1333–1336 (1987).
Postlethwaite, A. E., Keski-Oja, J., Moses, H. L. & Kang, A. H. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J. Exp. Med 165, 251–256 (1987).
Pierce, G. F. et al. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J. Cell Biol. 109, 429–440 (1989).
Puolakkainen, P. A. et al. Acceleration of wound healing in aged rats by topical application of transforming growth factor-beta(1). Wound Repair Regen. 3, 330–339 (1995).
Wahl, S. M. et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc. Natl Acad. Sci. USA 84, 5788–5792 (1987).
Rappolee, D. A., Mark, D., Banda, M. J. & Werb, Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science 241, 708–712 (1988).
Kane, C. J., Hebda, P. A., Mansbridge, J. N. & Hanawalt, P. C. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing. J. Cell Physiol. 148, 157–173 (1991).
Zambruno, G. et al. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J. Cell Biol. 129, 853–865 (1995).
Jeong, H. W. & Kim, I. S. TGF-beta1 enhances betaig-h3-mediated keratinocyte cell migration through the alpha3beta1 integrin and PI3K. J. Cell Biochem 92, 770–780 (2004).
Bandyopadhyay, B. et al. A “traffic control” role for TGFbeta3: orchestrating dermal and epidermal cell motility during wound healing. J. Cell Biol. 172, 1093–1105 (2006).
Heimark, R. L., Twardzik, D. R. & Schwartz, S. M. Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. Science 233, 1078–1080 (1986).
Roberts, A. B. et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).
Wang, X. J., Liefer, K. M., Tsai, S., O’Malley, B. W. & Roop, D. R. Development of gene-switch transgenic mice that inducibly express transforming growth factor beta1 in the epidermis. Proc. Natl Acad. Sci. USA 96, 8483–8488 (1999).
Lynch, S. E., Colvin, R. B. & Antoniades, H. N. Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds. J. Clin. Invest 84, 640–646 (1989).
Madri, J. A., Pratt, B. M. & Tucker, A. M. Phenotypic modulation of endothelial cells by transforming growth factor-beta depends upon the composition and organization of the extracellular matrix. J. Cell Biol. 106, 1375–1384 (1988).
Iruela-Arispe, M. L. & Sage, E. H. Endothelial cells exhibiting angiogenesis in vitro proliferate in response to TGF-beta 1. J. Cell Biochem 52, 414–430 (1993).
Lu, S. L. et al. Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation. Cancer Res 64, 4405–4410 (2004).
Cox, D. A., Kunz, S., Cerletti, N., McMaster, G. K. & Burk, R. R. Wound healing in aged animals-effects of locally applied transforming growth factor beta 2 in different model systems. Exs 61, 287–295 (1992).
Frank, S. et al. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J. Biol. Chem. 270, 12607–12613 (1995).
Pertovaara, L. et al. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J. Biol. Chem. 269, 6271–6274 (1994).
Strutz, F. et al. TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 59, 579–592 (2001).
Battegay, E. J., Raines, E. W., Seifert, R. A., Bowen-Pope, D. F. & Ross, R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 63, 515–524 (1990).
Ignotz, R. A. & Massagué, J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J. Biol. Chem. 261, 4337–4345 (1986).
Clark, R. A., McCoy, G. A., Folkvord, J. M. & McPherson, J. M. TGF-beta 1 stimulates cultured human fibroblasts to proliferate and produce tissue-like fibroplasia: a fibronectin matrix-dependent event. J. Cell Physiol. 170, 69–80 (1997).
Murata, H. et al. TGF-beta3 stimulates and regulates collagen synthesis through TGF-beta1-dependent and independent mechanisms. J. Invest Dermatol 108, 258–262 (1997).
Tyrone, J. W. et al. Transforming growth factor beta3 promotes fascial wound healing in a new animal model. Arch. Surg. 135, 1154–1159 (2000).
Edwards, D. R. et al. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. Embo j. 6, 1899–1904 (1987).
Lund, L. R. et al. Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. Embo j. 6, 1281–1286 (1987).
Overall, C. M., Wrana, J. L. & Sodek, J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J. Biol. Chem. 264, 1860–1869 (1989).
Wright, J. K., Cawston, T. E. & Hazleman, B. L. Transforming growth factor beta stimulates the production of the tissue inhibitor of metalloproteinases (TIMP) by human synovial and skin fibroblasts. Biochim. Biophys. Acta 1094, 207–210 (1991).
Shah, M., Foreman, D. M. & Ferguson, M. W. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J. Cell Sci. 108, 985–1002 (1995).
Montesano, R. & Orci, L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc. Natl Acad. Sci. USA 85, 4894–4897 (1988).
Meckmongkol, T. T., Harmon, R., McKeown-Longo, P. & Van De Water, L. The fibronectin synergy site modulates TGF-beta-dependent fibroblast contraction. Biochem Biophys. Res Commun. 360, 709–714 (2007).
Desmoulière, A., Geinoz, A., Gabbiani, F. & Gabbiani, G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).
Jakowlew, S. B. et al. Transforming growth factor-beta (TGF-beta) isoforms in rat liver regeneration: messenger RNA expression and activation of latent TGF-beta. Cell Regul. 2, 535–548 (1991).
Armendariz-Borunda, J. et al. Transforming growth factor beta gene expression is transiently enhanced at a critical stage during liver regeneration after CCl4 treatment. Lab Invest 69, 283–294 (1993).
Braun, L. et al. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc. Natl Acad. Sci. USA 85, 1539–1543 (1988).
Nishikawa, Y., Wang, M. & Carr, B. I. Changes in TGF-beta receptors of rat hepatocytes during primary culture and liver regeneration: increased expression of TGF-beta receptors associated with increased sensitivity to TGF-beta-mediated growth inhibition. J. Cell Physiol. 176, 612–623 (1998).
Grasl-Kraupp, B. et al. Levels of transforming growth factor beta and transforming growth factor beta receptors in rat liver during growth, regression by apoptosis and neoplasia. Hepatology 28, 717–726 (1998).
Riesle, E. et al. Increased expression of transforming growth factor beta s after acute oedematous pancreatitis in rats suggests a role in pancreatic repair. Gut 40, 73–79 (1997).
Friess, H. et al. Enhanced expression of TGF-betas and their receptors in human acute pancreatitis. Ann. Surg. 227, 95–104 (1998).
Gress, T. et al. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur. J. Clin. Invest 24, 679–685 (1994).
Wan, M. et al. Injury-activated transforming growth factor β controls mobilization of mesenchymal stem cells for tissue remodeling. Stem Cells 30, 2498–2511 (2012).
Bax, N. A. et al. In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1. Basic Res Cardiol. 106, 829–847 (2011).
Redini, F., Galera, P., Mauviel, A., Loyau, G. & Pujol, J. P. Transforming growth factor beta stimulates collagen and glycosaminoglycan biosynthesis in cultured rabbit articular chondrocytes. FEBS Lett. 234, 172–176 (1988).
Malemud, C. J., Killeen, W., Hering, T. M. & Purchio, A. F. Enhanced sulfated-proteoglycan core protein synthesis by incubation of rabbit chondrocytes with recombinant transforming growth factor-beta 1. J. Cell Physiol. 149, 152–159 (1991).
Buss, A. et al. TGF-beta1 and TGF-beta2 expression after traumatic human spinal cord injury. Spinal Cord. 46, 364–371 (2008).
Lehrmann, E. et al. Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia 24, 437–448 (1998).
Hannon, G. J. & Beach, D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371, 257–261 (1994).
Datto, M. B. et al. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl Acad. Sci. USA 92, 5545–5549 (1995).
Rich, J. N., Zhang, M., Datto, M. B., Bigner, D. D. & Wang, X. F. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J. Biol. Chem. 274, 35053–35058 (1999).
Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massagué, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).
Gomis, R. R., Alarcón, C., Nadal, C., Van Poznak, C. & Massagué, J. C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006).
Feng, X. H., Lin, X. & Derynck, R. Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. Embo j. 19, 5178–5193 (2000).
Pardali, K. et al. Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. J. Biol. Chem. 275, 29244–29256 (2000).
Reynisdóttir, I., Polyak, K., Iavarone, A. & Massagué, J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 9, 1831–1845 (1995).
Reynisdóttir, I. & Massagué, J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 11, 492–503 (1997).
Kamesaki, H., Nishizawa, K., Michaud, G. Y., Cossman, J. & Kiyono, T. TGF-beta 1 induces the cyclin-dependent kinase inhibitor p27Kip1 mRNA and protein in murine B cells. J. Immunol. 160, 770–777 (1998).
Scandura, J. M., Boccuni, P., Massagué, J. & Nimer, S. D. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc. Natl Acad. Sci. USA 101, 15231–15236 (2004).
Chen, C. R., Kang, Y., Siegel, P. M. & Massagué, J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110, 19–32 (2002).
Yagi, K. et al. c-myc is a downstream target of the Smad pathway. J. Biol. Chem. 277, 854–861 (2002).
Kang, Y., Chen, C. R. & Massagué, J. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915–926 (2003).
Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).
Siegel, P. M., Shu, W. & Massagué, J. Mad upregulation and Id2 repression accompany transforming growth factor (TGF)-beta-mediated epithelial cell growth suppression. J. Biol. Chem. 278, 35444–35450 (2003).
Seoane, J. et al. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat. Cell Biol. 3, 400–408 (2001).
Seoane, J., Le, H. V. & Massagué, J. Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419, 729–734 (2002).
Prabhu, S., Ignatova, A., Park, S. T. & Sun, X. H. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol. Cell Biol. 17, 5888–5896 (1997).
Asirvatham, A. J., Carey, J. P. & Chaudhary, J. ID1-, ID2-, and ID3-regulated gene expression in E2A positive or negative prostate cancer cells. Prostate 67, 1411–1420 (2007).
Iavarone, A. & Massagué, J. E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest. Mol. Cell Biol. 19, 916–922 (1999).
Bhowmick, N. A. et al. TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc. Natl Acad. Sci. USA 100, 15548–15553 (2003).
Ray, D. et al. Transforming growth factor beta facilitates beta-TrCP-mediated degradation of Cdc25A in a Smad3-dependent manner. Mol. Cell Biol. 25, 3338–3347 (2005).
Leof, E. B. et al. Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: a proposed model for indirect mitogenesis involving autocrine activity. Proc. Natl Acad. Sci. USA 83, 2453–2457 (1986).
Wildey, G. M., Patil, S. & Howe, P. H. Smad3 potentiates transforming growth factor beta (TGFbeta)-induced apoptosis and expression of the BH3-only protein Bim in WEHI 231 B lymphocytes. J. Biol. Chem. 278, 18069–18077 (2003).
Ramjaun, A. R., Tomlinson, S. & Eddaoudi, A. & Downward, J. Upregulation of two BH3-only proteins, Bmf and Bim, during TGF beta-induced apoptosis. Oncogene 26, 970–981 (2007).
Yoshimoto, T. et al. Involvement of smad2 and Erk/Akt cascade in TGF-β1-induced apoptosis in human gingival epithelial cells. Cytokine 75, 165–173 (2015).
Schiffer, M. et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J. Clin. Invest 108, 807–816 (2001).
Francis, J. M. et al. Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. J. Biol. Chem. 275, 39137–39145 (2000).
Schulz, R., Vogel, T., Dressel, R. & Krieglstein, K. TGF-beta superfamily members, ActivinA and TGF-beta1, induce apoptosis in oligodendrocytes by different pathways. Cell Tissue Res 334, 327–338 (2008).
Larisch, S. et al. A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat. Cell Biol. 2, 915–921 (2000).
Perlman, R., Schiemann, W. P., Brooks, M. W., Lodish, H. F. & Weinberg, R. A. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 3, 708–714 (2001).
Arsura, M., Wu, M. & Sonenshein, G. E. TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Immunity 5, 31–40 (1996).
Arsura, M., FitzGerald, M. J., Fausto, N. & Sonenshein, G. E. Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines. Cell Growth Differ. 8, 1049–1059 (1997).
Arsura, M. et al. Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22, 412–425 (2003).
Yoo, J. et al. Transforming growth factor-beta-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J. Biol. Chem. 278, 43001–43007 (2003).
Schiffer, M., Mundel, P., Shaw, A. S. & Böttinger, E. P. A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J. Biol. Chem. 279, 37004–37012 (2004).
Conery, A. R. et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat. Cell Biol. 6, 366–372 (2004).
Remy, I., Montmarquette, A. & Michnick, S. W. PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat. Cell Biol. 6, 358–365 (2004).
Valderrama-Carvajal, H. et al. Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nat. Cell Biol. 4, 963–969 (2002).
Bender, H., Wang, Z., Schuster, N. & Krieglstein, K. TIEG1 facilitates transforming growth factor-beta-mediated apoptosis in the oligodendroglial cell line OLI-neu. J. Neurosci. Res 75, 344–352 (2004).
Wang, Z., Spittau, B., Behrendt, M., Peters, B. & Krieglstein, K. Human TIEG2/KLF11 induces oligodendroglial cell death by downregulation of Bcl-XL expression. J. Neural Transm. (Vienna) 114, 867–875 (2007).
Chalaux, E. et al. A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mv1Lu cells. FEBS Lett. 457, 478–482 (1999).
Poulsen, K. T. et al. TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons. Neuron 13, 1245–1252 (1994).
Roussa, E., Farkas, L. M. & Krieglstein, K. TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8. Neurobiol. Dis. 16, 300–310 (2004).
Krieglstein, K., Farkas, L. & Unsicker, K. TGF-beta regulates the survival of ciliary ganglionic neurons synergistically with ciliary neurotrophic factor and neurotrophins. J. Neurobiol. 37, 563–572 (1998).
Bye, N., Zieba, M., Wreford, N. G. & Nichols, N. R. Resistance of the dentate gyrus to induced apoptosis during ageing is associated with increases in transforming growth factor-beta1 messenger RNA. Neuroscience 105, 853–862 (2001).
Shin, I., Bakin, A. V., Rodeck, U., Brunet, A. & Arteaga, C. L. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol. Biol. Cell 12, 3328–3339 (2001).
Lanvin, O. et al. TGF-beta1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines. Eur. J. Immunol. 33, 1372–1381 (2003).
Huang, Y. et al. Transforming growth factor-beta 1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities. J. Biol. Chem. 275, 18234–18242 (2000).
Saile, B., Matthes, N., El Armouche, H., Neubauer, K. & Ramadori, G. The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur. J. Cell Biol. 80, 554–561 (2001).
Letterio, J. J. & Roberts, A. B. Regulation of immune responses by TGF-beta. Annu Rev. Immunol. 16, 137–161 (1998).
Thomas, D. A. & Massagué, J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).
Ahmadzadeh, M. & Rosenberg, S. A. TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J. Immunol. 174, 5215–5223 (2005).
Genestier, L., Kasibhatla, S., Brunner, T. & Green, D. R. Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc. J. Exp. Med 189, 231–239 (1999).
Chen, C. H. et al. Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J. Exp. Med 197, 1689–1699 (2003).
Gorelik, L., Constant, S. & Flavell, R. A. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med 195, 1499–1505 (2002).
Gorelik, L., Fields, P. E. & Flavell, R. A. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165, 4773–4777 (2000).
Heath, V. L., Murphy, E. E., Crain, C., Tomlinson, M. G. & O’Garra, A. TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur. J. Immunol. 30, 2639–2649 (2000).
Chen, W. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med 198, 1875–1886 (2003).
Fantini, M. C. et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).
Zheng, S. G., Wang, J., Wang, P., Gray, J. D. & Horwitz, D. A. IL-2 is essential for TGF-beta to convert naive CD4+CD25- cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J. Immunol. 178, 2018–2027 (2007).
Davidson, T. S., DiPaolo, R. J., Andersson, J. & Shevach, E. M. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178, 4022–4026 (2007).
Sawamukai, N. et al. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD. Blood 119, 5575–5583 (2012).
Rich, S., Seelig, M., Lee, H. M. & Lin, J. Transforming growth factor beta 1 costimulated growth and regulatory function of staphylococcal enterotoxin B-responsive CD8+ T cells. J. Immunol. 155, 609–618 (1995).
Dardalhon, V. et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat. Immunol. 9, 1347–1355 (2008).
Chang, H. C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11, 527–534 (2010).
Goswami, R. et al. STAT6-dependent regulation of Th9 development. J. Immunol. 188, 968–975 (2012).
Veldhoen, M. et al. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).
Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 9, 641–649 (2008).
Volpe, E. et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol. 9, 650–657 (2008).
Kehrl, J. H., Thevenin, C., Rieckmann, P. & Fauci, A. S. Transforming growth factor-beta suppresses human B lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secreted form of Ig mRNA. J. Immunol. 146, 4016–4023 (1991).
Rehmann, J. A. & LeBien, T. W. Transforming growth factor-beta regulates normal human pre-B cell differentiation. Int Immunol. 6, 315–322 (1994).
Bouchard, C., Fridman, W. H. & Sautès, C. Mechanism of inhibition of lipopolysaccharide-stimulated mouse B-cell responses by transforming growth factor-beta 1. Immunol. Lett. 40, 105–110 (1994).
Lebman, D. A., Lee, F. D. & Coffman, R. L. Mechanism for transforming growth factor beta and IL-2 enhancement of IgA expression in lipopolysaccharide-stimulated B cell cultures. J. Immunol. 144, 952–959 (1990).
Zhong, Z. et al. Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers. Front Immunol. 12, 765044 (2021).
Ferreira-Gomes, M. et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat. Commun. 12, 1961 (2021).
Balkwill, F., Montfort, A. & Capasso, M. B regulatory cells in cancer. Trends Immunol. 34, 169–173 (2013).
Catalan, D. et al. Immunosuppressive Mechanisms of Regulatory B Cells. Front Immunol. 12, 611795 (2021).
Shang, J., Zha, H. & Sun, Y. Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer. Front Immunol. 11, 582657 (2020).
Wang, L., Fu, Y. & Chu, Y. Regulatory B Cells. Adv. Exp. Med. Biol. 1254, 87–103 (2020).
Tang, P. M. et al. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development. Nat. Commun. 8, 14677 (2017).
Trotta, R. et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J. Immunol. 181, 3784–3792 (2008).
Castriconi, R. et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc. Natl Acad. Sci. USA 100, 4120–4125 (2003).
Fujii, R. et al. An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression. Cancer Immunol. Immunother. 67, 675–689 (2018).
Piskurich, J. F., Wang, Y., Linhoff, M. W., White, L. C. & Ting, J. P. Identification of distinct regions of 5’ flanking DNA that mediate constitutive, IFN-gamma, STAT1, and TGF-beta-regulated expression of the class II transactivator gene. J. Immunol. 160, 233–240 (1998).
Nandan, D. & Reiner, N. E. TGF-beta attenuates the class II transactivator and reveals an accessory pathway of IFN-gamma action. J. Immunol. 158, 1095–1101 (1997).
Shaul, M. E. et al. Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology 5, e1232221 (2016).
Geissmann, F. et al. TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J. Immunol. 162, 4567–4575 (1999).
Takeuchi, M., Alard, P. & Streilein, J. W. TGF-beta promotes immune deviation by altering accessory signals of antigen-presenting cells. J. Immunol. 160, 1589–1597 (1998).
Espevik, T. et al. Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J. Exp. Med 166, 571–576 (1987).
Bogdan, C., Paik, J., Vodovotz, Y. & Nathan, C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J. Biol. Chem. 267, 23301–23308 (1992).
Nelson, B. J., Ralph, P., Green, S. J. & Nacy, C. A. Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1. J. Immunol. 146, 1849–1857 (1991).
Vodovotz, Y., Bogdan, C., Paik, J., Xie, Q. W. & Nathan, C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J. Exp. Med 178, 605–613 (1993).
Oswald, I. P., Gazzinelli, R. T., Sher, A. & James, S. L. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J. Immunol. 148, 3578–3582 (1992).
Tridandapani, S. et al. TGF-beta 1 suppresses [correction of supresses] myeloid Fc gamma receptor function by regulating the expression and function of the common gamma-subunit. J. Immunol. 170, 4572–4577 (2003).
Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).
Larsson, J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. Embo j. 20, 1663–1673 (2001).
Oshima, M., Oshima, H. & Taketo, M. M. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev. Biol. 179, 297–302 (1996).
Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
McLennan, I. S., Poussart, Y. & Koishi, K. Development of skeletal muscles in transforming growth factor-beta 1 (TGF-beta1) null-mutant mice. Dev. Dyn. 217, 250–256 (2000).
Sanford, L. P. et al. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124, 2659–2670 (1997).
Foitzik, K., Paus, R., Doetschman, T. & Dotto, G. P. The TGF-beta2 isoform is both a required and sufficient inducer of murine hair follicle morphogenesis. Dev. Biol. 212, 278–289 (1999).
Bartram, U. et al. Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice. Circulation 103, 2745–2752 (2001).
Jiao, K. et al. Tgfbeta signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development 133, 4585–4593 (2006).
Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat. Genet 11, 415–421 (1995).
Proetzel, G. et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat. Genet 11, 409–414 (1995).
Lindsay, M. E. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet 44, 922–927 (2012).
Boileau, C. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet 44, 916–921 (2012).
Al Maskari, R. et al. A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression. Eur. J. Hum. Genet 25, 157–160 (2016).
Rienhoff, H. Y. Jr. et al. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am. J. Med Genet A 161a, 2040–2046 (2013).
Bertoli-Avella, A. M. et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J. Am. Coll. Cardiol. 65, 1324–1336 (2015).
Kuechler, A. et al. Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome. Mol. Cell Probes 29, 330–334 (2015).
Loeys, B. L. et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med 355, 788–798 (2006).
Hara, H. et al. Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1. Hum. Genome Var. 6, 6 (2019).
Tran-Fadulu, V. et al. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J. Med Genet 46, 607–613 (2009).
Kirmani, S. et al. Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome. Am. J. Med Genet A 152a, 1016–1019 (2010).
Cousin, M. A. et al. Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys-Dietz syndrome (LDS) impairs canonical TGF-β signaling. Cold Spring Harb. Mol. Case Stud. 3, a001727 (2017).
Luo, X. et al. Identification of a Pathogenic TGFBR2 Variant in a Patient With Loeys-Dietz Syndrome. Front Genet 11, 479 (2020).
Cannaerts, E. et al. Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype. J. Med Genet 56, 220–227 (2019).
Granadillo, J. L. et al. Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants. Hum. Mutat. 39, 1875–1884 (2018).
Schepers, D. et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum. Mutat. 39, 621–634 (2018).
van de Laar, I. M. et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet 43, 121–126 (2011).
van de Laar, I. M. et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J. Med Genet 49, 47–57 (2012).
Aubart, M. et al. Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition. PLoS One 9, e96387 (2014).
Chung, B. H. et al. Hand and fibrillin-1 deposition abnormalities in Loeys-Dietz syndrome-expanding the clinical spectrum. Am. J. Med Genet A 164a, 461–466 (2014).
Barnett, C. P., Chitayat, D., Bradley, T. J., Wang, Y. & Hinek, A. Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment? Eur. J. Hum. Genet 19, 624–633 (2011).
Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet 37, 275–281 (2005).
Maleszewski, J. J., Miller, D. V., Lu, J., Dietz, H. C. & Halushka, M. K. Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). Am. J. Surg. Pathol. 33, 194–201 (2009).
Sellheyer, K. et al. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc. Natl Acad. Sci. USA 90, 5237–5241 (1993).
Ito, Y. et al. Overexpression of Smad2 reveals its concerted action with Smad4 in regulating TGF-beta-mediated epidermal homeostasis. Dev. Biol. 236, 181–194 (2001).
Erlebacher, A. & Derynck, R. Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype. J. Cell Biol. 132, 195–210 (1996).
Flügel-Koch, C., Ohlmann, A., Piatigorsky, J. & Tamm, E. R. Disruption of anterior segment development by TGF-beta1 overexpression in the eyes of transgenic mice. Dev. Dyn. 225, 111–125 (2002).
Vicencio, A. G. et al. Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? Am. J. Respir. Cell Mol. Biol. 31, 650–656 (2004).
Zeng, X., Gray, M., Stahlman, M. T. & Whitsett, J. A. TGF-beta1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo. Dev. Dyn. 221, 289–301 (2001).
Jhappan, C. et al. Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. Embo j. 12, 1835–1845 (1993).
Pierce, D. F. Jr. et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev. 7, 2308–2317 (1993).
Buggiano, V. et al. Impairment of mammary lobular development induced by expression of TGFbeta1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice. Int J. Cancer 92, 568–576 (2001).
Hall, B. E. et al. Conditional overexpression of TGF-beta1 disrupts mouse salivary gland development and function. Lab Invest 90, 543–555 (2010).
Wyss-Coray, T. et al. Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. Am. J. Pathol. 147, 53–67 (1995).
Saito, T. et al. Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1. J. Biol. Chem. 276, 11469–11472 (2001).
Janssens, K., ten Dijke, P., Ralston, S. H., Bergmann, C. & Van Hul, W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J. Biol. Chem. 278, 7718–7724 (2003).
Wallace, S. E. & Wilcox, W. R. In GeneReviews(®) (eds. M. P. Adam et al.) (University of Washington, Seattle Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved., 1993).
Janssens, K. et al. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat. Genet 26, 273–275 (2000).
McGowan, N. W. et al. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J. Clin. Endocrinol. Metab. 88, 3321–3326 (2003).
Tang, Y. et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med 15, 757–765 (2009).
Schmid, P. et al. TGF-beta s and TGF-beta type II receptor in human epidermis: differential expression in acute and chronic skin wounds. J. Pathol. 171, 191–197 (1993).
Pastar, I. et al. Attenuation of the transforming growth factor beta-signaling pathway in chronic venous ulcers. Mol. Med 16, 92–101 (2010).
Kim, B. C. et al. Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta Type II receptor expression. J. Cell Physiol. 195, 331–336 (2003).
Cowin, A. J. et al. Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chronic venous leg ulcers. J. Invest Dermatol 117, 1282–1289 (2001).
Bitar, M. S. & Labbad, Z. N. Transforming growth factor-beta and insulin-like growth factor-I in relation to diabetes-induced impairment of wound healing. J. Surg. Res 61, 113–119 (1996).
Jude, E. B., Blakytny, R., Bulmer, J., Boulton, A. J. & Ferguson, M. W. Transforming growth factor-beta 1, 2, 3 and receptor type I and II in diabetic foot ulcers. Diabet. Med 19, 440–447 (2002).
Liu, J. et al. Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1). Proc. Natl Acad. Sci. USA 108, 14560–14565 (2011).
Tredget, E. B. et al. Transforming growth factor-beta and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice. Wound Repair Regen. 13, 61–67 (2005).
Chan, T. et al. Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen. 10, 177–187 (2002).
Brown, R. L., Ormsby, I., Doetschman, T. C. & Greenhalgh, D. G. Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen. 3, 25–36 (1995).
Crowe, M. J., Doetschman, T. & Greenhalgh, D. G. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J. Invest Dermatol 115, 3–11 (2000).
Amendt, C., Mann, A., Schirmacher, P. & Blessing, M. Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J. Cell Sci. 115, 2189–2198 (2002).
Owens, P., Engelking, E., Han, G., Haeger, S. M. & Wang, X. J. Epidermal Smad4 deletion results in aberrant wound healing. Am. J. Pathol. 176, 122–133 (2010).
Ashcroft, G. S. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat. Cell Biol. 1, 260–266 (1999).
Ghahary, A., Shen, Y. J., Scott, P. G. & Tredget, E. E. Immunolocalization of TGF-beta 1 in human hypertrophic scar and normal dermal tissues. Cytokine 7, 184–190 (1995).
Schmid, P., Itin, P., Cherry, G., Bi, C. & Cox, D. A. Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am. J. Pathol. 152, 485–493 (1998).
Wang, R. et al. Hypertrophic scar tissues and fibroblasts produce more transforming growth factor-beta1 mRNA and protein than normal skin and cells. Wound Repair Regen. 8, 128–137 (2000).
Chin, G. S. et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast. Reconstr. Surg. 108, 423–429 (2001).
Xia, W., Phan, T. T., Lim, I. J., Longaker, M. T. & Yang, G. P. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen. 12, 546–556 (2004).
Younai, S. et al. Modulation of collagen synthesis by transforming growth factor-beta in keloid and hypertrophic scar fibroblasts. Ann. Plast. Surg. 33, 148–151 (1994).
Chodon, T., Sugihara, T., Igawa, H. H., Funayama, E. & Furukawa, H. Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance. Am. J. Pathol. 157, 1661–1669 (2000).
Colwell, A. S., Phan, T. T., Kong, W., Longaker, M. T. & Lorenz, P. H. Hypertrophic scar fibroblasts have increased connective tissue growth factor expression after transforming growth factor-beta stimulation. Plast. Reconstr. Surg. 116, 1387–1390 (2005). discussion 1391-1382.
Bettinger, D. A., Yager, D. R., Diegelmann, R. F. & Cohen, I. K. The effect of TGF-beta on keloid fibroblast proliferation and collagen synthesis. Plast. Reconstr. Surg. 98, 827–833 (1996).
Fujiwara, M., Muragaki, Y. & Ooshima, A. Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch. Dermatol Res 297, 161–169 (2005).
Hoyt, D. G. & Lazo, J. S. Alterations in pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor-beta precede bleomycin-induced pulmonary fibrosis in mice. J. Pharm. Exp. Ther. 246, 765–771 (1988).
Westergren-Thorsson, G. et al. Altered expression of small proteoglycans, collagen, and transforming growth factor-beta 1 in developing bleomycin-induced pulmonary fibrosis in rats. J. Clin. Invest 92, 632–637 (1993).
Broekelmann, T. J., Limper, A. H., Colby, T. V. & McDonald, J. A. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc. Natl Acad. Sci. USA 88, 6642–6646 (1991).
Coker, R. K. et al. Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung. Thorax 56, 549–556 (2001).
Corrin, B. et al. Immunohistochemical localization of transforming growth factor-beta 1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders. Histopathology 24, 145–150 (1994).
Utsugi, M. et al. C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 28, 754–761 (2003).
Togami, K., Yamaguchi, K., Chono, S. & Tada, H. Evaluation of permeability alteration and epithelial-mesenchymal transition induced by transforming growth factor-β(1) in A549, NCI-H441, and Calu-3 cells: Development of an in vitro model of respiratory epithelial cells in idiopathic pulmonary fibrosis. J. Pharm. Toxicol. Methods 86, 19–27 (2017).
Roy, S. G., Nozaki, Y. & Phan, S. H. Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int J. Biochem Cell Biol. 33, 723–734 (2001).
Kim, K. K. et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl Acad. Sci. USA 103, 13180–13185 (2006).
Lee, C. G. et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J. Exp. Med 200, 377–389 (2004).
Sime, P. J., Xing, Z., Graham, F. L., Csaky, K. G. & Gauldie, J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J. Clin. Invest 100, 768–776 (1997).
D’Alessandro-Gabazza, C. N. et al. Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 46, 397–406 (2012).
Li, M. et al. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J. Clin. Invest 121, 277–287 (2011).
Xu, L. et al. Transforming growth factor β3 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-γ/IL-4 balance. Immunol. Lett. 162, 27–33 (2014).
Zhao, J. et al. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 282, L585–L593 (2002).
Nakao, A. et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J. Clin. Invest 104, 5–11 (1999).
Yamamoto, T. et al. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int 49, 461–469 (1996).
Shihab, F. S. et al. Transforming growth factor-beta and matrix protein expression in acute and chronic rejection of human renal allografts. J. Am. Soc. Nephrol. 6, 286–294 (1995).
Yoshioka, K. et al. Transforming growth factor-beta protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 68, 154–163 (1993).
Iwano, M. et al. Intraglomerular expression of transforming growth factor-beta 1 (TGF-beta 1) mRNA in patients with glomerulonephritis: quantitative analysis by competitive polymerase chain reaction. Clin. Exp. Immunol. 97, 309–314 (1994).
Grande, J., Melder, D., Zinsmeister, A. & Killen, P. Transforming growth factor-beta 1 induces collagen IV gene expression in NIH-3T3 cells. Lab Invest 69, 387–395 (1993).
Nakamura, T., Miller, D., Ruoslahti, E. & Border, W. A. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int 41, 1213–1221 (1992).
Kagami, S. et al. Transforming growth factor-beta (TGF-beta) stimulates the expression of beta1 integrins and adhesion by rat mesangial cells. Exp. Cell Res 229, 1–6 (1996).
Okuda, S., Languino, L. R., Ruoslahti, E. & Border, W. A. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J. Clin. Invest 86, 453–462 (1990).
Marti, H. P., Lee, L., Kashgarian, M. & Lovett, D. H. Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase. Am. J. Pathol. 144, 82–94 (1994).
Zeisberg, M., Maeshima, Y., Mosterman, B. & Kalluri, R. Renal fibrosis. Extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am. J. Pathol. 160, 2001–2008 (2002).
Yang, J. & Liu, Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am. J. Pathol. 159, 1465–1475 (2001).
Kopp, J. B. et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest 74, 991–1003 (1996).
Mozes, M. M., Böttinger, E. P., Jacot, T. A. & Kopp, J. B. Renal expression of fibrotic matrix proteins and of transforming growth factor-beta (TGF-beta) isoforms in TGF-beta transgenic mice. J. Am. Soc. Nephrol. 10, 271–280 (1999).
Nagy, P., Schaff, Z. & Lapis, K. Immunohistochemical detection of transforming growth factor-beta 1 in fibrotic liver diseases. Hepatology 14, 269–273 (1991).
Castilla, A., Prieto, J. & Fausto, N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N. Engl. J. Med 324, 933–940 (1991).
Czaja, M. J. et al. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J. Cell Biol. 108, 2477–2482 (1989).
Sakaguchi, E. et al. Th1 down-regulation at the single-lymphocyte level in HCV-related liver cirrhosis and the effect of TGF-beta on Th1 response: possible implications for the development of hepatoma. Hepatol. Res 24, 282 (2002).
Ueberham, E. et al. Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology 37, 1067–1078 (2003).
Sanderson, N. et al. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc. Natl Acad. Sci. USA 92, 2572–2576 (1995).
El-Youssef, M., Mu, Y., Huang, L., Stellmach, V. & Crawford, S. E. Increased expression of transforming growth factor-beta1 and thrombospondin-1 in congenital hepatic fibrosis: possible role of the hepatic stellate cell. J. Pediatr. Gastroenterol. Nutr. 28, 386–392 (1999).
Teekakirikul, P. et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J. Clin. Invest 120, 3520–3529 (2010).
Kania, G. et al. Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ. Res 105, 462–470 (2009).
Zhao, W., Zhao, T., Chen, Y., Ahokas, R. A. & Sun, Y. Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol. Cell Biochem 317, 43–50 (2008).
Lijnen, P. J., Petrov, V. V. & Fagard, R. H. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol. Genet Metab. 71, 418–435 (2000).
Kuwahara, F. et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106, 130–135 (2002).
Sakata, Y. et al. Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor. Basic Res Cardiol. 103, 60–68 (2008).
Hagler, M. A. et al. TGF-β signalling and reactive oxygen species drive fibrosis and matrix remodelling in myxomatous mitral valves. Cardiovasc Res 99, 175–184 (2013).
Spriewald, B. M., Ensminger, S. M., Billing, J. S., Morris, P. J. & Wood, K. J. Increased expression of transforming growth factor-beta and eosinophil infiltration is associated with the development of transplant arteriosclerosis in long-term surviving cardiac allografts. Transplantation 76, 1105–1111 (2003).
Bobik, A. et al. Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation 99, 2883–2891 (1999).
Li, J. et al. Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis. Am. J. Transpl. 15, 3095–3111 (2015).
Chang, S. H. et al. Transforming growth factor-β-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation. Basic Res Cardiol. 112, 58 (2017).
Seeland, U. et al. Myocardial fibrosis in transforming growth factor-beta(1) (TGF-beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. Eur. J. Clin. Invest 32, 295–303 (2002).
Cucoranu, I. et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ. Res 97, 900–907 (2005).
Blyszczuk, P. et al. Transforming growth factor-β-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. Eur. Heart J. 38, 1413–1425 (2017).
Song, S. et al. Foxm1 is a critical driver of TGF-β-induced EndMT in endothelial cells through Smad2/3 and binds to the Snail promoter. J. Cell Physiol. 234, 9052–9064 (2019).
Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med 13, 952–961 (2007).
Varga, J., Rosenbloom, J. & Jimenez, S. A. Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J. 247, 597–604 (1987).
Goto, K. et al. Development and progression of immobilization-induced skin fibrosis through overexpression of transforming growth factor-ß1 and hypoxic conditions in a rat knee joint contracture model. Connect Tissue Res 58, 586–596 (2017).
Zhang, X. et al. Roles of TGF-β/Smad signaling pathway in pathogenesis and development of gluteal muscle contracture. Connect Tissue Res 56, 9–17 (2015).
Yoshikawa, H. et al. Role of TGF-beta1 in the development of pancreatic fibrosis in Otsuka Long-Evans Tokushima Fatty rats. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G549–G558 (2002).
Vogelmann, R., Ruf, D., Wagner, M., Adler, G. & Menke, A. Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G164–G172 (2001).
Van Laethem, J. L., Robberecht, P., Résibois, A. & Devière, J. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology 110, 576–582 (1996).
Shek, F. W. et al. Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am. J. Pathol. 160, 1787–1798 (2002).
Yao, J. C. et al. TGF-β signaling in myeloproliferative neoplasms contributes to myelofibrosis without disrupting the hematopoietic niche. J. Clin. Invest 132, e154092 (2022).
Ponce, C. C., de Lourdes, F. C. M., Ihara, S. S. & Silva, M. R. The relationship of the active and latent forms of TGF-β1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis. Med Oncol. 29, 2337–2344 (2012).
Shen, M., Liu, X., Zhang, H. & Guo, S. W. Transforming growth factor β1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum. Reprod. 31, 355–369 (2016).
Koski, H., Konttinen, Y. T., Gu, X. H., Hietanen, J. & Malmström, M. Transforming growth factor beta 2 in labial salivary glands in Sjögren’s syndrome. Ann. Rheum. Dis. 54, 744–747 (1995).
di Mola, F. F. et al. Transforming growth factor-betas and their signaling receptors are coexpressed in Crohn’s disease. Ann. Surg. 229, 67–75 (1999).
Gómez-Bernal, F. et al. Transforming growth factor beta 1 is associated with subclinical carotid atherosclerosis in patients with systemic lupus erythematosus. Arthritis Res Ther. 25, 64 (2023).
Liu, B. et al. Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model. World J. Gastroenterol. 19, 5828–5836 (2013).
Chida, T. et al. Critical role of CREBH-mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells. Hepatology 66, 1430–1443 (2017).
Mehta, A. K., Doherty, T., Broide, D. & Croft, M. Tumor necrosis factor family member LIGHT acts with IL-1β and TGF-β to promote airway remodeling during rhinovirus infection. Allergy 73, 1415–1424 (2018).
Ahodantin, J. et al. Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy. JCI Insight 7, e152738 (2022).
Huang, L. et al. CD8+ T cells with high TGF‑β1 expression cause lymph node fibrosis following HIV infection. Mol. Med Rep. 18, 77–86 (2018).
Kulkarni, A. B. et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl Acad. Sci. USA 90, 770–774 (1993).
Kulkarni, A. B. et al. Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. Am. J. Pathol. 146, 264–275 (1995).
Dang, H. et al. SLE-like autoantibodies and Sjögren’s syndrome-like lymphoproliferation in TGF-beta knockout mice. J. Immunol. 155, 3205–3212 (1995).
Laouar, Y. et al. TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 10865–10870 (2008).
Hahm, K. B. et al. Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49, 190–198 (2001).
Schramm, C. et al. Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G525–G535 (2003).
Ramalingam, R. et al. Dendritic cell-specific disruption of TGF-beta receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity. J. Immunol. 189, 3878–3893 (2012).
Ihara, S. et al. TGF-beta Signaling in Dendritic Cells Governs Colonic Homeostasis by Controlling Epithelial Differentiation and the Luminal Microbiota. J. Immunol. 196, 4603–4613 (2016).
Gorelik, L. & Flavell, R. A. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).
Turner, J. A. et al. Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. Immunity 53, 1202–1214.e1206 (2020).
Hahm, K. B. et al. Loss of TGF-beta signaling contributes to autoimmune pancreatitis. J. Clin. Invest 105, 1057–1065 (2000).
Gómez-Bernal, F. et al. Serum Levels of Transforming Growth Factor Beta 1 in Systemic Lupus Erythematosus Patients. Biomolecules 13, 73 (2022).
Manolova, I., Gerenova, J. & Ivanova, M. Serum levels of transforming growth factor-β1 (TGF-β1) in patients with systemic lupus erythematosus and Hashimoto’s thyroiditis. Eur. Cytokine Netw. 24, 69–74 (2013).
Becker-Merok, A., Eilertsen, G. & Nossent, J. C. Levels of transforming growth factor-beta are low in systemic lupus erythematosus patients with active disease. J. Rheumatol. 37, 2039–2045 (2010).
Lomelí-Nieto, J. A. et al. Transforming growth factor beta isoforms and TGF-βR1 and TGF-βR2 expression in systemic sclerosis patients. Clin. Exp. Med 23, 471–481 (2023).
Dziadzio, M., Smith, R. E., Abraham, D. J., Black, C. M. & Denton, C. P. Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatol. (Oxf.) 44, 1518–1524 (2005).
Kulozik, M., Hogg, A., Lankat-Buttgereit, B. & Krieg, T. Co-localization of transforming growth factor beta 2 with alpha 1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J. Clin. Invest 86, 917–922 (1990).
Kubo, M., Ihn, H., Yamane, K. & Tamaki, K. Upregulated expression of transforming growth factor-beta receptors in dermal fibroblasts of skin sections from patients with systemic sclerosis. J. Rheumatol. 29, 2558–2564 (2002).
Taketazu, F. et al. Enhanced expression of transforming growth factor-beta s and transforming growth factor-beta type II receptor in the synovial tissues of patients with rheumatoid arthritis. Lab Invest 70, 620–630 (1994).
Szekanecz, Z. et al. Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease. Clin. Immunol. Immunopathol. 76, 187–194 (1995).
Mieliauskaite, D., Venalis, P., Dumalakiene, I., Venalis, A. & Distler, J. Relationship between serum levels of TGF-beta1 and clinical parameters in patients with rheumatoid arthritis and Sjögren’s syndrome secondary to rheumatoid arthritis. Autoimmunity 42, 356–358 (2009).
He, J. et al. Clinical significance of the expression levels of serum transforming growth factor-β and CXC type chemokine ligand 13 in primary Sjogren’s syndrome patients. Clin. Rheumatol. 42, 3283–3288 (2023).
Ogawa, N. et al. Analysis of transforming growth factor beta and other cytokines in autoimmune exocrinopathy (Sjögren’s syndrome). J. Interferon Cytokine Res 15, 759–767 (1995).
Kader, H. A. et al. Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn’s disease and ulcerative colitis patients in remission versus active disease. Am. J. Gastroenterol. 100, 414–423 (2005).
Kanazawa, S. et al. VEGF, basic-FGF, and TGF-beta in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am. J. Gastroenterol. 96, 822–828 (2001).
Babyatsky, M. W., Rossiter, G. & Podolsky, D. K. Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology 110, 975–984 (1996).
Stadnicki, A., Machnik, G., Klimacka-Nawrot, E., Wolanska-Karut, A. & Labuzek, K. Transforming growth factor-beta1 and its receptors in patients with ulcerative colitis. Int Immunopharmacol. 9, 761–766 (2009).
Wiercińska-Drapało, A., Flisiak, R. & Prokopowicz, D. Effect of ulcerative colitis activity on plasma concentration of transforming growth factor beta1. Cytokine 14, 343–346 (2001).
Chowdhury, A., Fukuda, R. & Fukumoto, S. Growth factor mRNA expression in normal colorectal mucosa and in uninvolved mucosa from ulcerative colitis patients. J. Gastroenterol. 31, 353–360 (1996).
Bayer, E. M. et al. Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity. J. Hepatol. 28, 803–811 (1998).
Sakaguchi, K. et al. Serum level of transforming growth factor-beta1 (TGF-beta1) and the expression of TGF-beta receptor type II in peripheral blood mononuclear cells in patients with autoimmune hepatitis. Hepatogastroenterology 51, 1780–1783 (2004).
Vural, P., Degirmencioglu, S., Erden, S. & Gelincik, A. The relationship between transforming growth factor-beta1, vascular endothelial growth factor, nitric oxide and Hashimoto’s thyroiditis. Int Immunopharmacol. 9, 212–215 (2009).
Akinci, B. et al. Hashimoto’s thyroiditis, but not treatment of hypothyroidism, is associated with altered TGF-beta1 levels. Arch. Med Res 39, 397–401 (2008).
Ohtsuka, K., Gray, J. D., Stimmler, M. M., Toro, B. & Horwitz, D. A. Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J. Immunol. 160, 2539–2545 (1998).
Del Zotto, B. et al. TGF-beta1 production in inflammatory bowel disease: differing production patterns in Crohn’s disease and ulcerative colitis. Clin. Exp. Immunol. 134, 120–126 (2003).
Ohtsuka, K., Gray, J. D., Stimmler, M. M. & Horwitz, D. A. The relationship between defects in lymphocyte production of transforming growth factor-beta1 in systemic lupus erythematosus and disease activity or severity. Lupus 8, 90–94 (1999).
Kotlarz, D. et al. Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat. Genet 50, 344–348 (2018).
Bai, B. et al. Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis. Mol. Med Rep. 25, 116 (2022).
Elbeldi-Ferchiou, A. et al. Resistance to exogenous TGF-β effects in patients with systemic lupus erythematosus. J. Clin. Immunol. 31, 574–583 (2011).
Naviglio, S. et al. Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling. J. Crohns Colitis 8, 770–774 (2014).
Peres, R. S. et al. TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis. J. Autoimmun. 90, 49–58 (2018).
Rekik, R. et al. Impaired TGF-β signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22. Cytokine 108, 182–189 (2018).
Yalcin, A. D., Bisgin, A. & Gorczynski, R. M. IL-8, IL-10, TGF-β, and GCSF levels were increased in severe persistent allergic asthma patients with the anti-IgE treatment. Mediators Inflamm. 2012, 720976 (2012).
Yamaguchi, M. et al. Sputum levels of transforming growth factor-beta1 in asthma: relation to clinical and computed tomography findings. J. Investig. Allergol. Clin. Immunol. 18, 202–206 (2008).
Manuyakorn, W. et al. Serum TGF-beta1 in atopic asthma. Asian Pac. J. Allergy Immunol. 26, 185–189 (2008).
Redington, A. E. et al. Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid. Am. J. Respir. Crit. Care Med 156, 642–647 (1997).
Balzar, S. et al. Increased TGF-beta2 in severe asthma with eosinophilia. J. Allergy Clin. Immunol. 115, 110–117 (2005).
Torrego, A., Hew, M., Oates, T., Sukkar, M. & Fan Chung, K. Expression and activation of TGF-beta isoforms in acute allergen-induced remodelling in asthma. Thorax 62, 307–313 (2007).
Vignola, A. M. et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med 156, 591–599 (1997).
Jiang, K. et al. Changes in interleukin-17 and transforming growth factor beta 1 levels in serum and bronchoalveolar lavage fluid and their clinical significance among children with asthma. Transl. Pediatr. 2, 154–159 (2013).
Vignola, A. M. et al. Release of transforming growth factor-beta (TGF-beta) and fibronectin by alveolar macrophages in airway diseases. Clin. Exp. Immunol. 106, 114–119 (1996).
Minshall, E. M. et al. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 17, 326–333 (1997).
Ohno, I. et al. Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation. Am. J. Respir. Cell Mol. Biol. 15, 404–409 (1996).
Xie, S., Sukkar, M. B., Issa, R., Khorasani, N. M. & Chung, K. F. Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta. Am. J. Physiol. Lung Cell Mol. Physiol. 293, L245–L253 (2007).
Berger, P. et al. Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. Faseb j. 17, 2139–2141 (2003).
Janulaityte, I., Januskevicius, A., Kalinauskaite-Zukauske, V., Bajoriuniene, I. & Malakauskas, K. In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-β1 Signaling Pathway in Asthma. Int J. Mol. Sci. 21, 1837 (2020).
Januskevicius, A. et al. Eosinophils enhance WNT-5a and TGF-β1 genes expression in airway smooth muscle cells and promote their proliferation by increased extracellular matrix proteins production in asthma. BMC Pulm. Med 16, 94 (2016).
Bottoms, S. E., Howell, J. E., Reinhardt, A. K., Evans, I. C. & McAnulty, R. J. Tgf-Beta isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One 5, e9674 (2010).
Gagliardo, R. et al. The role of transforming growth factor-β1 in airway inflammation of childhood asthma. Int J. Immunopathol. Pharm. 26, 725–738 (2013).
Eusebio, M., Kraszula, L., Kupczyk, M., Kuna, P. & Pietruczuk, M. The effects of interleukin-10 or TGF-beta on anti-CD3/CD28 induced activation of CD8+CD28- and CD8+CD28+ T cells in allergic asthma. J. Biol. Regul. Homeost. Agents 27, 681–692 (2013).
Hung, C. H. et al. Altered pattern of monocyte differentiation and monocyte-derived TGF-β1 in severe asthma. Sci. Rep. 8, 919 (2018).
Ma, Y. et al. Immunization against TGF-β1 reduces collagen deposition but increases sustained inflammation in a murine asthma model. Hum. Vaccin Immunother. 12, 1876–1885 (2016).
Scherf, W., Burdach, S. & Hansen, G. Reduced expression of transforming growth factor beta 1 exacerbates pathology in an experimental asthma model. Eur. J. Immunol. 35, 198–206 (2005).
Luo, X. et al. In vivo disruption of TGF-beta signaling by Smad7 in airway epithelium alleviates allergic asthma but aggravates lung carcinogenesis in mouse. PLoS One 5, e10149 (2010).
Gao, P. et al. Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma. J. Immunol. 192, 4560–4570 (2014).
Nemeth, K. et al. Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc. Natl Acad. Sci. USA 107, 5652–5657 (2010).
Musiol, S. et al. TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure. Front Immunol. 12, 763243 (2021).
Whitehead, G. S. et al. A neutrophil/TGF-β axis limits the pathogenicity of allergen-specific CD4+ T cells. JCI Insight 7, e150251 (2022).
Yang, Z. C. et al. Transforming growth factor-β1 induces bronchial epithelial cells to mesenchymal transition by activating the Snail pathway and promotes airway remodeling in asthma. Mol. Med Rep. 8, 1663–1668 (2013).
Hackett, T. L. et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am. J. Respir. Crit. Care Med 180, 122–133 (2009).
Stumm, C. L. et al. Lung remodeling in a mouse model of asthma involves a balance between TGF-β1 and BMP-7. PLoS One 9, e95959 (2014).
Wnuk, D. et al. Enhanced asthma-related fibroblast to myofibroblast transition is the result of profibrotic TGF-β/Smad2/3 pathway intensification and antifibrotic TGF-β/Smad1/5/(8)9 pathway impairment. Sci. Rep. 10, 16492 (2020).
Ciprandi, G., De Amici, M., Tosca, M. & Marseglia, G. Serum transforming growth factor-beta levels depend on allergen exposure in allergic rhinitis. Int Arch. Allergy Immunol. 152, 66–70 (2010).
Salib, R. J., Kumar, S., Wilson, S. J. & Howarth, P. H. Nasal mucosal immunoexpression of the mast cell chemoattractants TGF-beta, eotaxin, and stem cell factor and their receptors in allergic rhinitis. J. Allergy Clin. Immunol. 114, 799–806 (2004).
Salib, R. J. Transforming growth factor-beta gene expression studies in nasal mucosal biopsies in naturally occurring allergic rhinitis. Ann. R. Coll. Surg. Engl. 89, 563–573 (2007).
Ouyang, Y., Nakao, A., Han, D. & Zhang, L. Transforming growth factor-β1 promotes nasal mucosal mast cell chemotaxis in murine experimental allergic rhinitis. ORL J. Otorhinolaryngol. Relat. Spec. 74, 117–123 (2012).
Ouyang, Y. et al. TGF-beta signaling may play a role in the development of goblet cell hyperplasia in a mouse model of allergic rhinitis. Allergol. Int 59, 313–319 (2010).
Wang, M., Gu, Z., Yang, J., Zhao, H. & Cao, Z. Changes among TGF-β1(+) Breg cells and helper T cell subsets in a murine model of allergic rhinitis with prolonged OVA challenge. Int Immunopharmacol. 69, 347–357 (2019).
Yang, M., Yang, C. & Mine, Y. Multiple T cell epitope peptides suppress allergic responses in an egg allergy mouse model by the elicitation of forkhead box transcription factor 3- and transforming growth factor-beta-associated mechanisms. Clin. Exp. Allergy 40, 668–678 (2010).
Barletta, B. et al. Probiotic VSL#3-induced TGF-β ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa. Mol. Nutr. Food Res 57, 2233–2244 (2013).
Pérez-Machado, M. A. et al. Reduced transforming growth factor-beta1-producing T cells in the duodenal mucosa of children with food allergy. Eur. J. Immunol. 33, 2307–2315 (2003).
Park, H. H. et al. TGF-β secreted by human umbilical cord blood-derived mesenchymal stem cells ameliorates atopic dermatitis by inhibiting secretion of TNF-α and IgE. Stem Cells 38, 904–916 (2020).
Sumiyoshi, K. et al. Transforming growth factor-beta1 suppresses atopic dermatitis-like skin lesions in NC/Nga mice. Clin. Exp. Allergy 32, 309–314 (2002).
Kim, H. S. et al. Human umbilical cord blood mesenchymal stem cell-derived PGE2 and TGF-β1 alleviate atopic dermatitis by reducing mast cell degranulation. Stem Cells 33, 1254–1266 (2015).
Lee, H. J., Lee, H. P., Ha, S. J., Byun, D. G. & Kim, J. W. Spontaneous expression of mRNA for IL-10, GM-CSF, TGF-beta, TGF-alpha, and IL-6 in peripheral blood mononuclear cells from atopic dermatitis. Ann. Allergy Asthma Immunol. 84, 553–558 (2000).
Peng, W. M., Maintz, L., Allam, J. P. & Novak, N. Attenuated TGF-β1 responsiveness of dendritic cells and their precursors in atopic dermatitis. Eur. J. Immunol. 43, 1374–1382 (2013).
Shafi, T. et al. Investigating dysregulation of TGF-β1/SMAD3 signaling in Atopic Dermatitis: A Molecular and Immunohistochemical Analysis. Clin. Exp. Immunol. https://doi.org/10.1093/cei/uxad130 (2023).
Akbarshahi, H., Sam, A., Chen, C., Rosendahl, A. H. & Andersson, R. Early activation of pulmonary TGF-β1/Smad2 signaling in mice with acute pancreatitis-associated acute lung injury. Mediat. Inflamm. 2014, 148029 (2014).
Hori, Y. et al. Macrophage-derived transforming growth factor-beta1 induces hepatocellular injury via apoptosis in rat severe acute pancreatitis. Surgery 127, 641–649 (2000).
van Laethem, J. L. et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology 108, 1873–1881 (1995).
Kanamaru, Y. et al. Blockade of TGF-beta signaling in T cells prevents the development of experimental glomerulonephritis. J. Immunol. 166, 2818–2823 (2001).
Kitamura, M., Sütö, T., Yokoo, T., Shimizu, F. & Fine, L. G. Transforming growth factor-beta 1 is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells. J. Immunol. 156, 2964–2971 (1996).
Zhang, W. et al. Staphylococcus aureus Infection Initiates Hypoxia-Mediated Transforming Growth Factor-β1 Upregulation to Trigger Osteomyelitis. mSystems 7, e0038022 (2022).
Brandes, M. E., Allen, J. B., Ogawa, Y. & Wahl, S. M. Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J. Clin. Invest 87, 1108–1113 (1991).
Yan, J. et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat. Med 20, 1001–1008 (2014).
Weiss, R., Lifshitz, V. & Frenkel, D. TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis. Brain Behav. Immun. 25, 1017–1024 (2011).
Grammas, P. & Ovase, R. Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer’s disease brain. Am. J. Pathol. 160, 1583–1587 (2002).
Rendón-Ramirez, E. J. et al. TGF-β Blood Levels Distinguish Between Influenza A (H1N1)pdm09 Virus Sepsis and Sepsis due to Other Forms of Community-Acquired Pneumonia. Viral Immunol. 28, 248–254 (2015).
Carlson, C. M. et al. Transforming growth factor-β: activation by neuraminidase and role in highly pathogenic H5N1 influenza pathogenesis. PLoS Pathog. 6, e1001136 (2010).
Furuya, Y. et al. Prevention of Influenza Virus-Induced Immunopathology by TGF-β Produced during Allergic Asthma. PLoS Pathog. 11, e1005180 (2015).
Richer, M. J., Straka, N., Fang, D., Shanina, I. & Horwitz, M. S. Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-beta. Diabetes 57, 1302–1311 (2008).
Shi, Y. et al. Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor beta-coxsackie-adenovirus receptor pathway. Circulation 121, 2624–2634 (2010).
Beckham, J. D., Tuttle, K. & Tyler, K. L. Reovirus activates transforming growth factor beta and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection. J. Virol. 83, 5035–5045 (2009).
Stanifer, M. L. et al. Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF-β dependent pro-survival signaling. Cell Microbiol 18, 1831–1845 (2016).
Chen, Y. et al. Mechanism of exosomes from adipose-derived mesenchymal stem cells on sepsis-induced acute lung injury by promoting TGF-β secretion in macrophages. Surgery 174, 1208–1219 (2023).
Sanfilippo, A. M., Furuya, Y., Roberts, S., Salmon, S. L. & Metzger, D. W. Allergic Lung Inflammation Reduces Tissue Invasion and Enhances Survival from Pulmonary Pneumococcal Infection in Mice, Which Correlates with Increased Expression of Transforming Growth Factor β1 and SiglecF(low) Alveolar Macrophages. Infect. Immun. 83, 2976–2983 (2015).
Wang, B. et al. Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection. Proc. Natl Acad. Sci. USA 107, 5937–5942 (2010).
Nakane, A. et al. Transforming growth factor beta is protective in host resistance against Listeria monocytogenes infection in mice. Infect. Immun. 64, 3901–3904 (1996).
Zhong, Y., Cantwell, A. & Dube, P. H. Transforming growth factor beta and CD25 are important for controlling systemic dissemination following Yersinia enterocolitica infection of the gut. Infect. Immun. 78, 3716–3725 (2010).
Shao, X., Rivera, J., Niang, R., Casadevall, A. & Goldman, D. L. A dual role for TGF-beta1 in the control and persistence of fungal pneumonia. J. Immunol. 175, 6757–6763 (2005).
Omer, F. M. & Riley, E. M. Transforming growth factor beta production is inversely correlated with severity of murine malaria infection. J. Exp. Med 188, 39–48 (1998).
Namangala, B., Sugimoto, C. & Inoue, N. Effects of exogenous transforming growth factor beta on Trypanosoma congolense infection in mice. Infect. Immun. 75, 1878–1885 (2007).
Buzoni-Gatel, D. et al. Murine ileitis after intracellular parasite infection is controlled by TGF-beta-producing intraepithelial lymphocytes. Gastroenterology 120, 914–924 (2001).
Cekanaviciute, E. et al. Astrocytic TGF-β signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection. J. Immunol. 193, 139–149 (2014).
Zhao, M. et al. The Effect of TGF-β on Treg Cells in Adverse Pregnancy Outcome upon Toxoplasma gondii Infection. Front Microbiol 8, 901 (2017).
Xu, X. et al. TGF-β1 improving abnormal pregnancy outcomes induced by Toxoplasma gondii infection: Regulating NKG2D/DAP10 and killer subset of decidual NK cells. Cell Immunol. 317, 9–17 (2017).
Heitmann, L. et al. TGF-β-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection. Am. J. Pathol. 181, 897–906 (2012).
Wu, H. P. et al. Plasma transforming growth factor-beta1 level in patients with severe community-acquired pneumonia and association with disease severity. J. Formos. Med Assoc. 108, 20–27 (2009).
de Pablo, R. et al. Sepsis-induced acute respiratory distress syndrome with fatal outcome is associated to increased serum transforming growth factor beta-1 levels. Eur. J. Intern Med 23, 358–362 (2012).
Gauthier, T. et al. TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis. Sci. Signal 16, eade0385 (2023).
Ahmad, S., Choudhry, M. A., Shankar, R. & Sayeed, M. M. Transforming growth factor-beta negatively modulates T-cell responses in sepsis. FEBS Lett. 402, 213–218 (1997).
Lowrance, J. H., O’Sullivan, F. X., Caver, T. E., Waegell, W. & Gresham, H. D. Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice. J. Exp. Med 180, 1693–1703 (1994).
Li, N. et al. Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors. Proc. Natl Acad. Sci. USA 112, 238–243 (2015).
Zhang, M. et al. TGF-β1 promoted the infection of bovine mammary epithelial cells by Staphylococcus aureus through increasing expression of cells’ fibronectin and integrin β1. Vet. Microbiol 237, 108420 (2019).
Owyang, S. Y. et al. Dendritic cell-derived TGF-β mediates the induction of mucosal regulatory T-cell response to Helicobacter infection essential for maintenance of immune tolerance in mice. Helicobacter 25, e12763 (2020).
Beswick, E. J., Pinchuk, I. V., Earley, R. B., Schmitt, D. A. & Reyes, V. E. Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect. Immun. 79, 2737–2745 (2011).
Liu, Y., Islam, E. A., Jarvis, G. A., Gray-Owen, S. D. & Russell, M. W. Neisseria gonorrhoeae selectively suppresses the development of Th1 and Th2 cells, and enhances Th17 cell responses, through TGF-β-dependent mechanisms. Mucosal. Immunol. 5, 320–331 (2012).
Balkhi, M. Y., Sinha, A. & Natarajan, K. Dominance of CD86, transforming growth factor- beta 1, and interleukin-10 in Mycobacterium tuberculosis secretory antigen-activated dendritic cells regulates T helper 1 responses to mycobacterial antigens. J. Infect. Dis. 189, 1598–1609 (2004).
Roberts, T., Beyers, N., Aguirre, A. & Walzl, G. Immunosuppression during active tuberculosis is characterized by decreased interferon- gamma production and CD25 expression with elevated forkhead box P3, transforming growth factor- beta, and interleukin-4 mRNA levels. J. Infect. Dis. 195, 870–878 (2007).
Denney, L., Branchett, W., Gregory, L. G., Oliver, R. A. & Lloyd, C. M. Epithelial-derived TGF-β1 acts as a pro-viral factor in the lung during influenza A infection. Mucosal. Immunol. 11, 523–535 (2018).
Thomas, B. J. et al. Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses. Am. J. Respir. Cell Mol. Biol. 41, 339–347 (2009).
Lewis, G. M., Macal, M., Hesser, C. R. & Zuñiga, E. I. Constitutive but not inducible attenuation of transforming growth factor β signaling increases natural killer cell responses without directly affecting dendritic cells early after persistent viral infection. J. Virol. 89, 3343–3355 (2015).
Marcoe, J. P. et al. TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat. Immunol. 13, 843–850 (2012).
Kekow, J. et al. Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proc. Natl Acad. Sci. USA 87, 8321–8325 (1990).
Kekow, J. et al. Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J. Clin. Invest 87, 1010–1016 (1991).
Bedke, N. et al. Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response. PLoS One 7, e44580 (2012).
Grunwell, J. R. et al. TGF-β1 Suppresses the Type I IFN Response and Induces Mitochondrial Dysfunction in Alveolar Macrophages. J. Immunol. 200, 2115–2128 (2018).
Witkowski, M. et al. Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells. Nature 600, 295–301 (2021).
Moriuchi, M. & Moriuchi, H. Cell-type-dependent effect of transforming growth factor beta, a major cytokine in breast milk, on human immunodeficiency virus type 1 infection of mammary epithelial MCF-7 cells or macrophages. J. Virol. 78, 13046–13052 (2004).
Yim, L. Y. et al. Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4(+) T Cells. J. Virol. 97, e0027023 (2023).
Cheung, K. W. et al. α(4)β(7)(+) CD4(+) Effector/Effector Memory T Cells Differentiate into Productively and Latently Infected Central Memory T Cells by Transforming Growth Factor β1 during HIV-1 Infection. J. Virol. 92, e01510–e01517 (2018).
Moriuchi, M. & Moriuchi, H. Transforming growth factor-beta enhances human T-cell leukemia virus type I infection. J. Med Virol. 67, 427–430 (2002).
Lin, W. et al. HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology 134, 803–811 (2008).
Trinh, Q. D. et al. TGF-β1 Promotes Zika Virus Infection in Immortalized Human First-Trimester Trophoblasts via the Smad Pathway. Cells 11, 3026 (2022).
Pham, N. T. K. et al. The Epithelial-to-Mesenchymal Transition-Like Process Induced by TGF-β1 Enhances Rubella Virus Binding and Infection in A549 Cells via the Smad Pathway. Microorganisms 9, 662 (2021).
Flynn, R. J. & Mulcahy, G. The roles of IL-10 and TGF-beta in controlling IL-4 and IFN-gamma production during experimental Fasciola hepatica infection. Int J. Parasitol. 38, 1673–1680 (2008).
Pang, N. et al. TGF-β/Smad signaling pathway regulates Th17/Treg balance during Echinococcus multilocularis infection. Int Immunopharmacol. 20, 248–257 (2014).
Barbosa, B. F. et al. IL10, TGF beta1, and IFN gamma modulate intracellular signaling pathways and cytokine production to control Toxoplasma gondii infection in BeWo trophoblast cells. Biol. Reprod. 92, 82 (2015).
Barral-Netto, M. et al. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science 257, 545–548 (1992).
Walther, M. et al. Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–296 (2005).
Tsutsui, N. & Kamiyama, T. Transforming growth factor beta-induced failure of resistance to infection with blood-stage Plasmodium chabaudi in mice. Infect. Immun. 67, 2306–2311 (1999).
Akhurst, R. J., Fee, F. & Balmain, A. Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis. Nature 331, 363–365 (1988).
Cui, W. et al. Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Genes Dev. 9, 945–955 (1995).
Fowlis, D. J., Cui, W., Johnson, S. A., Balmain, A. & Akhurst, R. J. Altered epidermal cell growth control in vivo by inducible expression of transforming growth factor beta 1 in the skin of transgenic mice. Cell Growth Differ. 7, 679–687 (1996).
Boulanger, C. A. & Smith, G. H. Reducing mammary cancer risk through premature stem cell senescence. Oncogene 20, 2264–2272 (2001).
Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J. & Massagué, J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl Acad. Sci. USA 100, 8430–8435 (2003).
Weeks, B. H., He, W., Olson, K. L. & Wang, X. J. Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis. Cancer Res 61, 7435–7443 (2001).
Gobbi, H. et al. Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia. J. Natl Cancer Inst. 91, 2096–2101 (1999).
Goudie, D. R. et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat. Genet 43, 365–369 (2011).
Goudie, D. Multiple Self-Healing Squamous Epithelioma (MSSE): A Digenic Trait Associated with Loss of Function Mutations in TGFBR1 and Variants at a Second Linked Locus on the Long Arm of Chromosome 9. Genes (Basel) 11, 1410 (2020).
Lu, S. L. et al. HNPCC associated with germline mutation in the TGF-beta type II receptor gene. Nat. Genet 19, 17–18 (1998).
Woodford-Richens, K. et al. Analysis of genetic and phenotypic heterogeneity in juvenile polyposis. Gut 46, 656–660 (2000).
Howe, J. R. et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J. Med Genet 41, 484–491 (2004).
Engle, S. J. et al. Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 59, 3379–3386 (1999).
Glick, A. B. et al. Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc. Natl Acad. Sci. USA 90, 6076–6080 (1993).
Forrester, E. et al. Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 65, 2296–2302 (2005).
Muñoz, N. M. et al. Transforming growth factor beta receptor type II inactivation induces the malignant transformation of intestinal neoplasms initiated by Apc mutation. Cancer Res 66, 9837–9844 (2006).
Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).
Lu, S. L. et al. Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 20, 1331–1342 (2006).
Bian, Y. et al. Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69, 5918–5926 (2009).
Guasch, G. et al. Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 12, 313–327 (2007).
Go, C. et al. Aberrant cell cycle progression contributes to the early-stage accelerated carcinogenesis in transgenic epidermis expressing the dominant negative TGFbetaRII. Oncogene 19, 3623–3631 (2000).
Amendt, C., Schirmacher, P., Weber, H. & Blessing, M. Expression of a dominant negative type II TGF-beta receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development. Oncogene 17, 25–34 (1998).
Kanzler, S. et al. Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 20, 5015–5024 (2001).
Hahm, K. B. et al. Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice. Aliment Pharm. Ther. 16, 115–127 (2002).
Biswas, S. et al. Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 64, 4687–4692 (2004).
Gorska, A. E. et al. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am. J. Pathol. 163, 1539–1549 (2003).
Zhu, Y., Richardson, J. A., Parada, L. F. & Graff, J. M. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703–714 (1998).
Wolfraim, L. A. et al. Loss of Smad3 in acute T-cell lymphoblastic leukemia. N. Engl. J. Med 351, 552–559 (2004).
Takaku, K. et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res 59, 6113–6117 (1999).
Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).
Alberici, P. et al. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene 25, 1841–1851 (2006).
Xu, X. et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19, 1868–1874 (2000).
Braun, L., Dürst, M., Mikumo, R., Crowley, A. & Robinson, M. Regulation of growth and gene expression in human papillomavirus-transformed keratinocytes by transforming growth factor-beta: implications for the control of papillomavirus infection. Mol. Carcinog. 6, 100–111 (1992).
Souza, R. F. et al. A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms. Gastroenterology 112, 40–45 (1997).
Kim, B. G. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441, 1015–1019 (2006).
Matsuzaki, K. et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46, 48–57 (2007).
Achyut, B. R. et al. Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling. PLoS Genet 9, e1003251 (2013).
Glick, A. B., Weinberg, W. C., Wu, I. H., Quan, W. & Yuspa, S. H. Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res 56, 3645–3650 (1996).
Katakura, Y., Nakata, E., Miura, T. & Shirahata, S. Transforming growth factor beta triggers two independent-senescence programs in cancer cells. Biochem Biophys. Res Commun. 255, 110–115 (1999).
Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).
Moustakas, A. & Kardassis, D. Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc. Natl Acad. Sci. USA 95, 6733–6738 (1998).
Kang, S. H. et al. Rapid induction of p21WAF1 but delayed down-regulation of Cdc25A in the TGF-beta-induced cell cycle arrest of gastric carcinoma cells. Br. J. Cancer 80, 1144–1149 (1999).
Damdinsuren, B. et al. TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells. Oncol. Rep. 15, 401–408 (2006).
Hishikawa, K. et al. Connective tissue growth factor induces apoptosis in human breast cancer cell line MCF-7. J. Biol. Chem. 274, 37461–37466 (1999).
Zhang, H. et al. Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene 25, 6101–6112 (2006).
Kim, S. G. et al. Transforming growth factor-beta 1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells. Mol. Biol. Cell 15, 420–434 (2004).
Jang, C. W. et al. TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nat. Cell Biol. 4, 51–58 (2002).
David, C. J. et al. TGF-β Tumor Suppression through a Lethal EMT. Cell 164, 1015–1030 (2016).
Tachibana, I. et al. Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J. Clin. Invest 99, 2365–2374 (1997).
Kim, B. C., Mamura, M., Choi, K. S., Calabretta, B. & Kim, S. J. Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol. Cell Biol. 22, 1369–1378 (2002).
Chipuk, J. E., Bhat, M., Hsing, A. Y., Ma, J. & Danielpour, D. Bcl-xL blocks transforming growth factor-beta 1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells. J. Biol. Chem. 276, 26614–26621 (2001).
Spender, L. C. et al. TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL. Cell Death Differ. 16, 593–602 (2009).
Ohgushi, M. et al. Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol. Cell Biol. 25, 10017–10028 (2005).
Saltzman, A. et al. Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation. Exp. Cell Res 242, 244–254 (1998).
Kanamaru, C., Yasuda, H. & Fujita, T. Involvement of Smad proteins in TGF-beta and activin A-induced apoptosis and growth inhibition of liver cells. Hepatol. Res 23, 211–219 (2002).
Bakhshayesh, M., Zaker, F., Hashemi, M., Katebi, M. & Solaimani, M. TGF- β1-mediated apoptosis associated with SMAD-dependent mitochondrial Bcl-2 expression. Clin. Lymphoma Myeloma Leuk. 12, 138–143 (2012).
Cui, W., Kemp, C. J., Duffie, E., Balmain, A. & Akhurst, R. J. Lack of transforming growth factor-beta 1 expression in benign skin tumors of p53null mice is prognostic for a high risk of malignant conversion. Cancer Res 54, 5831–5836 (1994).
Cui, W. et al. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86, 531–542 (1996).
Capocasale, R. J. et al. Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T cells from Sézary patients. Proc. Natl Acad. Sci. USA 92, 5501–5505 (1995).
Kadin, M. E. et al. Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc. Natl Acad. Sci. USA 91, 6002–6006 (1994).
Fukai, Y. et al. Reduced expression of transforming growth factor-beta receptors is an unfavorable prognostic factor in human esophageal squamous cell carcinoma. Int J. Cancer 104, 161–166 (2003).
Tanaka, S., Mori, M., Mafune, K., Ohno, S. & Sugimachi, K. A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma. Br. J. Cancer 82, 1557–1560 (2000).
Souza, R. F. et al. Alterations of transforming growth factor-beta 1 receptor type II occur in ulcerative colitis-associated carcinomas, sporadic colorectal neoplasms, and esophageal carcinomas, but not in gastric neoplasms. Hum. Cell 9, 229–236 (1996).
Myeroff, L. L. et al. A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 55, 5545–5547 (1995).
Grady, W. M. et al. Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Res 58, 3101–3104 (1998).
Salovaara, R. et al. Frequent loss of SMAD4/DPC4 protein in colorectal cancers. Gut 51, 56–59 (2002).
Takagi, Y. et al. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology 111, 1369–1372 (1996).
Goggins, M. et al. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58, 5329–5332 (1998).
Venkatasubbarao, K. et al. Novel mutations in the polyadenine tract of the transforming growth factor beta type II receptor gene are found in a subpopulation of human pancreatic adenocarcinomas. Genes Chromosomes Cancer 22, 138–144 (1998).
Imai, Y., Tsurutani, N., Oda, H., Inoue, T. & Ishikawa, T. Genetic instability and mutation of the TGF-beta-receptor-II gene in ampullary carcinomas. Int J. Cancer 76, 407–411 (1998).
Lazzereschi, D. et al. Human malignant thyroid tumors displayed reduced levels of transforming growth factor beta receptor type II messenger RNA and protein. Cancer Res 57, 2071–2076 (1997).
Kim, I. Y. et al. Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients. Clin. Cancer Res 4, 1625–1630 (1998).
Guo, Y., Jacobs, S. C. & Kyprianou, N. Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-beta1) type I and type II receptors in human prostate cancer. Int J. Cancer 71, 573–579 (1997).
Gobbi, H. et al. Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas. Histopathology 36, 168–177 (2000).
Lynch, M. A. et al. Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma. Cancer Res 58, 4227–4232 (1998).
Chen, T. et al. Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases. Int J. Cancer 93, 653–661 (2001).
Wang, D. et al. Mutation and downregulation of the transforming growth factor beta type II receptor gene in primary squamous cell carcinomas of the head and neck. Carcinogenesis 18, 2285–2290 (1997).
Qiu, W., Schönleben, F., Li, X. & Su, G. H. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Cancer Lett. 245, 163–170 (2007).
Xie, W. et al. Frequent alterations of Smad signaling in human head and neck squamous cell carcinomas: a tissue microarray analysis. Oncol. Res 14, 61–73 (2003).
Sun, L. et al. Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J. Biol. Chem. 269, 26449–26455 (1994).
Steiner, M. S. & Barrack, E. R. Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol. Endocrinol. 6, 15–25 (1992).
Chang, H. L. et al. Increased transforming growth factor beta expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells. Cancer Res 53, 4391–4398 (1993).
Kleeff, J. et al. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18, 5363–5372 (1999).
Datto, M. B., Hu, P. P., Kowalik, T. F., Yingling, J. & Wang, X. F. The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B. Mol. Cell Biol. 17, 2030–2037 (1997).
Missero, C. Ramon y Cajal, S. & Dotto, G. P. Escape from transforming growth factor beta control and oncogene cooperation in skin tumor development. Proc. Natl Acad. Sci. USA 88, 9613–9617 (1991).
Kurokawa, M. et al. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature 394, 92–96 (1998).
Alexandrow, M. G., Kawabata, M., Aakre, M. & Moses, H. L. Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc. Natl Acad. Sci. USA 92, 3239–3243 (1995).
Schlegel, N. C. et al. Id2 suppression of p15 counters TGF-beta-mediated growth inhibition of melanoma cells. Pigment Cell Melanoma Res 22, 445–453 (2009).
Ewen, M. E., Oliver, C. J., Sluss, H. K., Miller, S. J. & Peeper, D. S. p53-dependent repression of CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. Genes Dev. 9, 204–217 (1995).
Kretzschmar, M., Doody, J., Timokhina, I. & Massague, J. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 13, 804–816 (1999).
Dalal, B. I., Keown, P. A. & Greenberg, A. H. Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am. J. Pathol. 143, 381–389 (1993).
Walker, R. A. & Dearing, S. J. Transforming growth factor beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur. J. Cancer 28, 641–644 (1992).
Friess, H. et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105, 1846–1856 (1993).
Wagner, M., Kleeff, J., Friess, H., Büchler, M. W. & Korc, M. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 19, 370–376 (1999).
Tateishi, M. et al. The progression of invasiveness regarding the role of transforming growth factor beta receptor type II in gastric cancer. Eur. J. Surg. Oncol. 26, 377–380 (2000).
Welch, D. R., Fabra, A. & Nakajima, M. Transforming growth factor beta stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc. Natl Acad. Sci. USA 87, 7678–7682 (1990).
Tang, B. et al. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J. Clin. Invest 112, 1116–1124 (2003).
Oft, M., Heider, K. H. & Beug, H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol. 8, 1243–1252 (1998).
Han, G. et al. Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J. Clin. Invest 115, 1714–1723 (2005).
Caulín, C., Scholl, F. G., Frontelo, P., Gamallo, C. & Quintanilla, M. Chronic exposure of cultured transformed mouse epidermal cells to transforming growth factor-beta 1 induces an epithelial-mesenchymal transdifferentiation and a spindle tumoral phenotype. Cell Growth Differ. 6, 1027–1035 (1995).
Cheng, J. C., Auersperg, N. & Leung, P. C. TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells. PLoS One 7, e42436 (2012).
Qiao, B., Johnson, N. W. & Gao, J. Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-beta1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions. Int J. Oncol. 37, 663–668 (2010).
Vincent, T. et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat. Cell Biol. 11, 943–950 (2009).
Arrick, B. A. et al. Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor beta 1. J. Cell Biol. 118, 715–726 (1992).
Tu, W. H. et al. The loss of TGF-beta signaling promotes prostate cancer metastasis. Neoplasia 5, 267–277 (2003).
Huntley, S. P. et al. Attenuated type II TGF-beta receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination. Int J. Cancer 110, 170–176 (2004).
Hoosein, N. M. et al. Differential sensitivity of subclasses of human colon carcinoma cell lines to the growth inhibitory effects of transforming growth factor-beta 1. Exp. Cell Res 181, 442–453 (1989).
Takaku, K. et al. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92, 645–656 (1998).
Lewis, M. P. et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br. J. Cancer 90, 822–832 (2004).
Stuelten, C. H. et al. Transient tumor-fibroblast interactions increase tumor cell malignancy by a TGF-Beta mediated mechanism in a mouse xenograft model of breast cancer. PLoS One 5, e9832 (2010).
Löhr, M. et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res 61, 550–555 (2001).
Igarashi, A., Okochi, H., Bradham, D. M. & Grotendorst, G. R. Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol. Biol. Cell 4, 637–645 (1993).
Chantry, D., Turner, M., Abney, E. & Feldmann, M. Modulation of cytokine production by transforming growth factor-beta. J. Immunol. 142, 4295–4300 (1989).
Sieuwerts, A. M., Klijn, J. G., Henzen-Logmans, S. C. & Foekens, J. A. Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro. Breast Cancer Res Treat. 55, 9–20 (1999).
Cheng, N. et al. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24, 5053–5068 (2005).
Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67, 10123–10128 (2007).
Go, C., Li, P. & Wang, X. J. Blocking transforming growth factor beta signaling in transgenic epidermis accelerates chemical carcinogenesis: a mechanism associated with increased angiogenesis. Cancer Res 59, 2861–2868 (1999).
Ueki, N. et al. Excessive production of transforming growth-factor beta 1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim Biophys. Acta 1137, 189–196 (1992).
Padua, D. et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).
Haak-Frendscho, M., Wynn, T. A., Czuprynski, C. J. & Paulnock, D. Transforming growth factor-beta 1 inhibits activation of macrophage cell line RAW 264.7 for cell killing. Clin. Exp. Immunol. 82, 404–410 (1990).
Torre-Amione, G. et al. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc. Natl Acad. Sci. USA 87, 1486–1490 (1990).
Donkor, M. K., Sarkar, A. & Li, M. O. Tgf-β1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development. Oncoimmunology 1, 162–171 (2012).
Sarkar, A., Donkor, M. K. & Li, M. O. T cell- but not tumor cell-produced TGF-β1 promotes the development of spontaneous mammary cancer. Oncotarget 2, 1339–1351 (2011).
Arteaga, C. L. et al. Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J. Clin. Invest 92, 2569–2576 (1993).
Ghiringhelli, F. et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J. Exp. Med 202, 919–929 (2005).
Hsiao, Y. W. et al. Interactions of host IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression during tumor spontaneous regression. Cancer Immunol. Immunother. 57, 1091–1104 (2008).
Czarniecki, C. W., Chiu, H. H., Wong, G. H., McCabe, S. M. & Palladino, M. A. Transforming growth factor-beta 1 modulates the expression of class II histocompatibility antigens on human cells. J. Immunol. 140, 4217–4223 (1988).
Ma, D. & Niederkorn, J. Y. Transforming growth factor-beta down-regulates major histocompatibility complex class I antigen expression and increases the susceptibility of uveal melanoma cells to natural killer cell-mediated cytolysis. Immunology 86, 263–269 (1995).
Bogdahn, U. et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 13, 132–142 (2011).
Niu, N. K. et al. Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study. Drug Des. Devel Ther. 9, 4441–4470 (2015).
Yang, Z. et al. Preparation, characterization, and in-vitro cytotoxicity of nanoliposomes loaded with anti-tubercular drugs and TGF-β1 siRNA for improving spinal tuberculosis therapy. BMC Infect. Dis. 22, 824 (2022).
Guoyou, Z. et al. Modulation of transforming growth factor-beta1 production by vector-based RNAi in hypertrophic scar fibroblasts: a therapeutic potential strategy for hypertrophic scar. J. Dermatol Sci. 48, 67–70 (2007).
Loiselle, A. E. et al. Development of antisense oligonucleotide (ASO) technology against Tgf-β signaling to prevent scarring during flexor tendon repair. J. Orthop. Res 33, 859–866 (2015).
Jeong, H. S. et al. Effect of antisense TGF-beta1 oligodeoxynucleotides in streptozotocin- induced diabetic rat kidney. J. Korean Med Sci. 19, 374–383 (2004).
Isaka, Y. et al. Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction. Kidney Int 58, 1885–1892 (2000).
Han, D. C., Hoffman, B. B., Hong, S. W., Guo, J. & Ziyadeh, F. N. Therapy with antisense TGF-beta1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice. Am. J. Physiol. Ren. Physiol. 278, F628–F634 (2000).
Akagi, Y. et al. Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 50, 148–155 (1996).
Giaccone, G. et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur. J. Cancer 51, 2321–2329 (2015).
Olivares, J. et al. Phase I trial of TGF-beta 2 antisense GM-CSF gene-modified autologous tumor cell (TAG) vaccine. Clin. Cancer Res 17, 183–192 (2011).
Senzer, N. et al. Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer. Mol. Ther. 20, 679–686 (2012).
Rocconi, R. P. et al. Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer. Gynecol. Oncol. 161, 676–680 (2021).
Martin, C. J. et al. Selective inhibition of TGFbeta1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci. Transl. Med 12, eaay8456 (2020).
Welsh, B. T. et al. Nonclinical Development of SRK-181: An Anti-Latent TGFbeta1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors. Int J. Toxicol. 40, 226–241 (2021).
Li, A. et al. Selective targeting of GARP-LTGFbeta axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8(+) T cell antitumor immunity. J. Immunother. Cancer 10, e005433 (2022).
Elez, E. et al. Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial. Ann. Oncol. 26, 132–140 (2015).
Hussain, M. et al. Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer. Clin. Cancer Res 22, 3192–3200 (2016).
Khanna, D. et al. STRATUS: A Phase II Study of Abituzumab in Patients With Systemic Sclerosis-associated Interstitial Lung Disease. J. Rheumatol. 48, 1295–1298 (2021).
Uhl, W., Zuhlsdorf, M., Koernicke, T., Forssmann, U. & Kovar, A. Safety, tolerability, and pharmacokinetics of the novel alphav-integrin antibody EMD 525797 (DI17E6) in healthy subjects after ascending single intravenous doses. Invest N. Drugs 32, 347–354 (2014).
Manegold, C. et al. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer. Invest N. Drugs 31, 175–182 (2013).
Vansteenkiste, J. et al. Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO). Ann. Oncol. 26, 1734–1740 (2015).
Vermorken, J. B. et al. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann. Oncol. 25, 682–688 (2014).
Stupp, R. et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 2712–2718 (2010).
Reardon, D. A. et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 26, 5610–5617 (2008).
Nabors, L. B. et al. A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 118, 5601–5607 (2012).
Gilbert, M. R. et al. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery. J. Neurooncol 106, 147–153 (2012).
MacDonald, T. J. et al. Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol. 15, 1438–1444 (2013).
Nabors, L. B. et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol. 17, 708–717 (2015).
Khasraw, M. et al. Cilengitide with metronomic temozolomide, procarbazine, and standard radiotherapy in patients with glioblastoma and unmethylated MGMT gene promoter in ExCentric, an open-label phase II trial. J. Neurooncol 128, 163–171 (2016).
Stupp, R. et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 15, 1100–1108 (2014).
Kim, K. B. et al. A randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma. Melanoma Res 22, 294–301 (2012).
Friess, H. et al. A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 6, 285 (2006).
Bradley, D. A. et al. Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest N. Drugs 29, 1432–1440 (2011).
Alva, A. et al. Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium. Invest N. Drugs 30, 749–757 (2012).
Li, C. et al. Increased activation of latent TGF-β1 by αVβ3 in human Crohn’s disease and fibrosis in TNBS colitis can be prevented by cilengitide. Inflamm. Bowel Dis. 19, 2829–2839 (2013).
Bagnato, G. L. et al. Dual αvβ3 and αvβ5 blockade attenuates fibrotic and vascular alterations in a murine model of systemic sclerosis. Clin. Sci. (Lond.) 132, 231–242 (2018).
MacDonald, W. J. et al. Broad spectrum integrin inhibitor GLPG-0187 bypasses immune evasion in colorectal cancer by TGF-β signaling mediated downregulation of PD-L1. Am. J. Cancer Res 13, 2938–2947 (2023).
Verschleiser, B. et al. Pan-integrin inhibitor GLPG-0187 promotes T-cell killing of mismatch repair-deficient colorectal cancer cells by suppression of SMAD/TGF-β signaling. Am. J. Cancer Res 13, 2878–2885 (2023).
Belmadani, S. et al. A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. Am. J. Pathol. 171, 777–789 (2007).
Ruschkowski, B. A. et al. Thrombospondin-1 Plays a Major Pathogenic Role in Experimental and Human Bronchopulmonary Dysplasia. Am. J. Respir. Crit. Care Med 205, 685–699 (2022).
Song, S. et al. Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease. Cell Death Dis. 13, 663 (2022).
Xie, X. S. et al. LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. Arch. Pharm. Res 33, 275–284 (2010).
Lu, A., Miao, M., Schoeb, T. R., Agarwal, A. & Murphy-Ullrich, J. E. Blockade of TSP1-dependent TGF-β activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am. J. Pathol. 178, 2573–2586 (2011).
Zhang, Y. et al. P2Y4/TSP-1/TGF-β1/pSmad2/3 pathway contributes to acute generalized seizures induced by kainic acid. Brain Res Bull. 149, 106–119 (2019).
Liao, F. et al. LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats. Exp. Ther. Med 12, 2537–2543 (2016).
Jiang, N. et al. Blockade of thrombospondin-1 ameliorates high glucose-induced peritoneal fibrosis through downregulation of TGF-β1/Smad3 signaling pathway. J. Cell Physiol. 235, 364–379 (2020).
Narmada, B. C., Chia, S. M., Tucker-Kellogg, L. & Yu, H. HGF regulates the activation of TGF-β1 in rat hepatocytes and hepatic stellate cells. J. Cell Physiol. 228, 393–401 (2013).
Kondou, H. et al. A blocking peptide for transforming growth factor-beta1 activation prevents hepatic fibrosis in vivo. J. Hepatol. 39, 742–748 (2003).
Xu, X. et al. Investigating the potential of LSKL peptide as a novel hypertrophic scar treatment. Biomed. Pharmacother. 124, 109824 (2020).
Kuroki, H. et al. Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor β signal activation and liver regeneration after hepatectomy in an experimental model. Br. J. Surg. 102, 813–825 (2015).
Lu, A. et al. Inhibition of Transforming Growth Factor-β Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma. Am. J. Pathol. 186, 678–690 (2016).
Fu, P. Y. et al. Far upstream element-binding protein 1 facilitates hepatocellular carcinoma invasion and metastasis. Carcinogenesis 41, 950–960 (2020).
Gu, J. et al. Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop. J. Exp. Clin. Cancer Res 41, 259 (2022).
Daniel, C. et al. Antisense oligonucleotides against thrombospondin-1 inhibit activation of tgf-beta in fibrotic renal disease in the rat in vivo. Am. J. Pathol. 163, 1185–1192 (2003).
Agin, M., Yucel, A., Gumus, M., Yuksekkaya, H. A. & Tumgor, G. The Effect of Enteral Nutrition Support Rich in TGF-β in the Treatment of Inflammatory Bowel Disease in Childhood. Med. (Kaunas.) 55, 620 (2019).
Fell, J. M. et al. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn’s disease. Aliment Pharm. Ther. 14, 281–289 (2000).
Hartman, C. et al. Nutritional supplementation with polymeric diet enriched with transforming growth factor-beta 2 for children with Crohn’s disease. Isr. Med Assoc. J. 10, 503–507 (2008).
Ferreira, T. M. R. et al. Effect of Oral Nutrition Supplements and TGF-β2 on Nutrition and Inflammatory Patterns in Patients With Active Crohn’s Disease. Nutr. Clin. Pr. 35, 885–893 (2020).
Borrelli, O. et al. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn’s disease: a randomized controlled open-label trial. Clin. Gastroenterol. Hepatol. 4, 744–753 (2006).
Pigneur, B. et al. Mucosal Healing and Bacterial Composition in Response to Enteral Nutrition Vs Steroid-based Induction Therapy-A Randomised Prospective Clinical Trial in Children With Crohn’s Disease. J. Crohns Colitis 13, 846–855 (2019).
Beaupel, N. et al. Preoperative oral polymeric diet enriched with transforming growth factor-beta 2 (Modulen) could decrease postoperative morbidity after surgery for complicated ileocolonic Crohn’s disease. Scand. J. Gastroenterol. 52, 5–10 (2017).
Okamoto, A. et al. Suppression of serum IgE response and systemic anaphylaxis in a food allergy model by orally administered high-dose TGF-beta. Int Immunol. 17, 705–712 (2005).
Rekima, A. et al. Long-term reduction in food allergy susceptibility in mice by combining breastfeeding-induced tolerance and TGF-β-enriched formula after weaning. Clin. Exp. Allergy 47, 565–576 (2017).
Penttila, I. Effects of transforming growth factor-beta and formula feeding on systemic immune responses to dietary beta-lactoglobulin in allergy-prone rats. Pediatr. Res 59, 650–655 (2006).
Verhasselt, V. Neonatal tolerance under breastfeeding influence: the presence of allergen and transforming growth factor-beta in breast milk protects the progeny from allergic asthma. J. Pediatr. 156, S16–S20 (2010).
Morita, Y. et al. TGF-β Concentration in Breast Milk is Associated With the Development of Eczema in Infants. Front Pediatr. 6, 162 (2018).
Saarinen, K. M., Vaarala, O., Klemetti, P. & Savilahti, E. Transforming growth factor-beta1 in mothers’ colostrum and immune responses to cows’ milk proteins in infants with cows’ milk allergy. J. Allergy Clin. Immunol. 104, 1093–1098 (1999).
Ferguson, M. W. et al. Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies. Lancet 373, 1264–1274 (2009).
So, K. et al. Avotermin for scar improvement following scar revision surgery: a randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial. Plast. Reconstr. Surg. 128, 163–172 (2011).
Bush, J. et al. Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial. Plast. Reconstr. Surg. 126, 1604–1615 (2010).
McCollum, P. T. et al. Randomized phase II clinical trial of avotermin versus placebo for scar improvement. Br. J. Surg. 98, 925–934 (2011).
Robson, M. C. et al. Safety and effect of transforming growth factor-beta(2) for treatment of venous stasis ulcers. Wound Repair Regen. 3, 157–167 (1995).
Wang, X. et al. Demineralized bone matrix combined bone marrow mesenchymal stem cells, bone morphogenetic protein-2 and transforming growth factor-β3 gene promoted pig cartilage defect repair. PLoS One 9, e116061 (2014).
Luo, Z. et al. Mechano growth factor (MGF) and transforming growth factor (TGF)-β3 functionalized silk scaffolds enhance articular hyaline cartilage regeneration in rabbit model. Biomaterials 52, 463–475 (2015).
Kuruvilla, A. P. et al. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc. Natl Acad. Sci. USA 88, 2918–2921 (1991).
Srivastava, V., Khanna, M., Sharma, S. & Kumar, B. Resolution of immune response by recombinant transforming growth factor-beta (rTGF-β) during influenza A virus infection. Indian J. Med Res 136, 641–648 (2012).
Morris, J. C. et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One 9, e90353 (2014).
Formenti, S. C. et al. Focal Irradiation and Systemic TGFbeta Blockade in Metastatic Breast Cancer. Clin. Cancer Res 24, 2493–2504 (2018).
Rice, L. M. et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J. Clin. Invest 125, 2795–2807 (2015).
Trachtman, H. et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79, 1236–1243 (2011).
Lacouture, M. E. et al. Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor beta by the monoclonal antibody fresolimumab (GC1008). Cancer Immunol. Immunother. 64, 437–446 (2015).
Bauer, T. M. et al. Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors. J. Immunother. Cancer 11, e007353 (2023).
Denton, C. P. et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007).
Voelker, J. et al. Anti-TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy. J. Am. Soc. Nephrol. 28, 953–962 (2017).
Mascarenhas, J. et al. A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis. Clin. Cancer Res 29, 3622–3632 (2023).
Li, Y. et al. Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate peritendinous adhesion. Bone Res 11, 24 (2023).
Lu, L. et al. The temporal effects of anti-TGF-beta1, 2, and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J. Am. Coll. Surg. 201, 391–397 (2005).
Wang, L. et al. Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia. Stem Cells Transl. Med 6, 394–404 (2017).
Deng, S., Zhang, H., Han, W., Guo, C. & Deng, C. Transforming Growth Factor-β-Neutralizing Antibodies Improve Alveolarization in the Oxygen-Exposed Newborn Mouse Lung. J. Interferon Cytokine Res 39, 106–116 (2019).
Nelson, C. A. et al. Inhibiting TGF-β activity improves respiratory function in mdx mice. Am. J. Pathol. 178, 2611–2621 (2011).
Cook, J. R. et al. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler Thromb. Vasc. Biol. 35, 911–917 (2015).
Wang, X. et al. Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease. J. Clin. Invest 128, 846–860 (2018).
Becerikli, M. et al. TGF-beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration. J. Orthop. Res 40, 1810–1826 (2022).
Sahbani, K., Cardozo, C. P., Bauman, W. A. & Tawfeek, H. A. Inhibition of TGF-β Signaling Attenuates Disuse-induced Trabecular Bone Loss After Spinal Cord Injury in Male Mice. Endocrinology 163, bqab230 (2022).
Grafe, I. et al. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat. Med 20, 670–675 (2014).
Wahl, S. M., Allen, J. B., Costa, G. L., Wong, H. L. & Dasch, J. R. Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta. J. Exp. Med 177, 225–230 (1993).
Xie, L. et al. Systemic neutralization of TGF-β attenuates osteoarthritis. Ann. N. Y Acad. Sci. 1376, 53–64 (2016).
Ferreira, R. R. et al. In Chagas disease, transforming growth factor beta neutralization reduces Trypanosoma cruzi infection and improves cardiac performance. Front Cell Infect. Microbiol 12, 1017040 (2022).
Ravi, R. et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFbeta enhance the efficacy of cancer immunotherapy. Nat. Commun. 9, 741 (2018).
Paz-Ares, L. et al. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-beta and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial. J. Thorac. Oncol. 15, 1210–1222 (2020).
Kang, Y. K. et al. Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFbeta and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer. Clin. Cancer Res 26, 3202–3210 (2020).
Yoo, C. et al. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with pretreated biliary tract cancer. J. Immunother. Cancer 8, e000564 (2020).
Redman, J. M. et al. Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-beta blockade in HPV-unrelated head and neck cancer. J. Clin. Invest 132, e161400 (2022).
Strauss, J. et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors. Clin. Cancer Res 24, 1287–1295 (2018).
Wu, Z. H. et al. Development of the Novel Bifunctional Fusion Protein BR102 That Simultaneously Targets PD-L1 and TGF-β for Anticancer Immunotherapy. Cancers (Basel) 14, 4964 (2022).
Chen, X. et al. Secretion of bispecific protein of anti-PD-1 fused with TGF-beta trap enhances antitumor efficacy of CAR-T cell therapy. Mol. Ther. Oncolyt. 21, 144–157 (2021).
Fukushima, K. et al. The use of an antifibrosis agent to improve muscle recovery after laceration. Am. J. Sports Med 29, 394–402 (2001).
Ruehle, M. A. et al. Decorin-supplemented collagen hydrogels for the co-delivery of bone morphogenetic protein-2 and microvascular fragments to a composite bone-muscle injury model with impaired vascularization. Acta Biomater. 93, 210–221 (2019).
Ahmed, Z. et al. Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds. Neurobiol. Dis. 64, 163–176 (2014).
Qiu, S. S., Dotor, J. & Hontanilla, B. Effect of P144® (Anti-TGF-β) in an “In Vivo” Human Hypertrophic Scar Model in Nude Mice. PLoS One 10, e0144489 (2015).
Arce, C. et al. Anti-TGFβ (Transforming Growth Factor β) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome. Arterioscler Thromb. Vasc. Biol. 41, e440–e452 (2021).
Li, L. et al. Postinfarction gene therapy with adenoviral vector expressing decorin mitigates cardiac remodeling and dysfunction. Am. J. Physiol. Heart Circ. Physiol. 297, H1504–H1513 (2009).
Yan, W. et al. Decorin gene delivery inhibits cardiac fibrosis in spontaneously hypertensive rats by modulation of transforming growth factor-beta/Smad and p38 mitogen-activated protein kinase signaling pathways. Hum. Gene Ther. 20, 1190–1200 (2009).
Hermida, N. et al. A synthetic peptide from transforming growth factor-beta1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats. Cardiovasc Res 81, 601–609 (2009).
Nili, N. et al. Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty. Am. J. Pathol. 163, 869–878 (2003).
Recalde, S. et al. Transforming growth factor-β inhibition decreases diode laser-induced choroidal neovascularization development in rats: P17 and P144 peptides. Invest Ophthalmol. Vis. Sci. 52, 7090–7097 (2011).
Aojula, A. et al. Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile communicating hydrocephalus. Fluids Barriers CNS 13, 9 (2016).
Botfield, H. et al. Decorin prevents the development of juvenile communicating hydrocephalus. Brain 136, 2842–2858 (2013).
Murillo-Cuesta, S. et al. Transforming growth factor β1 inhibition protects from noise-induced hearing loss. Front Aging Neurosci. 7, 32 (2015).
Border, W. A. et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360, 361–364 (1992).
Juárez, P. et al. Soluble betaglycan reduces renal damage progression in db/db mice. Am. J. Physiol. Ren. Physiol. 292, F321–F329 (2007).
Baltanás, A. et al. A synthetic peptide from transforming growth factor-β1 type III receptor inhibits NADPH oxidase and prevents oxidative stress in the kidney of spontaneously hypertensive rats. Antioxid. Redox Signal 19, 1607–1618 (2013).
Li, D. et al. TGF-β1 peptide-based inhibitor P144 ameliorates renal fibrosis after ischemia-reperfusion injury by modulating alternatively activated macrophages. Cell Prolif. 55, e13299 (2022).
Zhang, Y., McCormick, L. L. & Gilliam, A. C. Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J. Invest Dermatol 121, 713–719 (2003).
Jang, Y. O. et al. Effect of Function-Enhanced Mesenchymal Stem Cells Infected With Decorin-Expressing Adenovirus on Hepatic Fibrosis. Stem Cells Transl. Med 5, 1247–1256 (2016).
Kolb, M., Margetts, P. J., Sime, P. J. & Gauldie, J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L1327–L1334 (2001).
Ezquerro, I. J. et al. A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury. Cytokine 22, 12–20 (2003).
Hirsch, C. S., Ellner, J. J., Blinkhorn, R. & Toossi, Z. In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor beta. Proc. Natl Acad. Sci. USA 94, 3926–3931 (1997).
Bandyopadhyay, A. et al. Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 62, 4690–4695 (2002).
Liu, Z. et al. An Oncolytic Adenovirus Encoding Decorin and Granulocyte Macrophage Colony Stimulating Factor Inhibits Tumor Growth in a Colorectal Tumor Model by Targeting Pro-Tumorigenic Signals and via Immune Activation. Hum. Gene Ther. 28, 667–680 (2017).
Zhang, W. et al. Efficacy of an Oncolytic Adenovirus Driven by a Chimeric Promoter and Armed with Decorin Against Renal Cell Carcinoma. Hum. Gene Ther. 31, 651–663 (2020).
Yang, Y. et al. Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases. Hum. Gene Ther. 26, 813–825 (2015).
Narayan, V. et al. PSMA-targeting TGFbeta-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med 28, 724–734 (2022).
Wang, F. L. et al. TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer. Cancer Immunol. Immunother. 56, 1785–1793 (2007).
Tian, F. et al. Vaccination with transforming growth factor-beta insensitive dendritic cells suppresses pulmonary metastases of renal carcinoma in mice. Cancer Lett. 271, 333–341 (2008).
Reid, R. R. et al. Reduction of hypertrophic scar via retroviral delivery of a dominant negative TGF-beta receptor II. J. Plast. Reconstr. Aesthet. Surg. 60, 64–72 (2007). discussion 73-64.
Santini, V. et al. Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes. Clin. Cancer Res 25, 6976–6985 (2019).
Nadal, E. et al. A phase Ib/II study of galunisertib in combination with nivolumab in solid tumors and non-small cell lung cancer. BMC Cancer 23, 708 (2023).
Kelley, R. K. et al. A Phase 2 Study of Galunisertib (TGF-beta1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma. Clin. Transl. Gastroenterol. 10, e00056 (2019).
Faivre, S. et al. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int 39, 1468–1477 (2019).
Yamazaki, T. et al. Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial. Lancet Oncol. 23, 1189–1200 (2022).
Melisi, D. et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br. J. Cancer 119, 1208–1214 (2018).
Wick, A. et al. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Invest N. Drugs 38, 1570–1579 (2020).
Brandes, A. A. et al. A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 18, 1146–1156 (2016).
Kovacs, R. J. et al. Cardiac Safety of TGF-beta Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovasc Toxicol. 15, 309–323 (2015).
Tolcher, A. W. et al. A phase 1 study of anti-TGFbeta receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors. Cancer Chemother. Pharm. 79, 673–680 (2017).
Suzuki, E. et al. A novel small-molecule inhibitor of transforming growth factor beta type I receptor kinase (SM16) inhibits murine mesothelioma tumor growth in vivo and prevents tumor recurrence after surgical resection. Cancer Res 67, 2351–2359 (2007).
Uhl, M. et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64, 7954–7961 (2004).
Tanaka, H. et al. Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol. Rep. 24, 1637–1643 (2010).
Halder, S. K., Beauchamp, R. D. & Datta, P. K. A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia 7, 509–521 (2005).
Lee, J. E. et al. Vactosertib, TGF-β receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer. Biomed. Pharmacother. 162, 114716 (2023).
Zhang, P. et al. The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment. Biomaterials 284, 121518 (2022).
Chen, J. et al. TGF-β Signaling Activation Confers Anlotinib Resistance in Gastric Cancer. Pharm. Res 40, 689–699 (2023).
Fu, K. et al. SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model. Arterioscler Thromb. Vasc. Biol. 28, 665–671 (2008).
Engebretsen, K. V. et al. Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5. J. Mol. Cell Cardiol. 76, 148–157 (2014).
Atis, M. et al. Targeting the blood-brain barrier disruption in hypertension by ALK5/TGF-Β type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore. Brain Res 1794, 148071 (2022).
Wu, D. et al. TGF-β1-PML SUMOylation-peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis. J. Cell Physiol. 234, 6263–6273 (2019).
Ha, K. B. et al. EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation. Endocrinol. Metab. (Seoul.) 37, 96–111 (2022).
Nassar, K. et al. A TGF-β receptor 1 inhibitor for prevention of proliferative vitreoretinopathy. Exp. Eye Res 123, 72–86 (2014).
Maeda, S., Hayashi, M., Komiya, S., Imamura, T. & Miyazono, K. Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. Embo j. 23, 552–563 (2004).
Lee, A. J. et al. Sustained Delivery of SB-431542, a Type I Transforming Growth Factor Beta-1 Receptor Inhibitor, to Prevent Arthrofibrosis. Tissue Eng. Part A 27, 1411–1421 (2021).
Anscher, M. S. et al. Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury. Int J. Radiat. Oncol. Biol. Phys. 71, 829–837 (2008).
Park, S. A. et al. EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cell Mol. Life Sci. 72, 2023–2039 (2015).
Alyoussef, A. Blocking TGF-β type 1 receptor partially reversed skin tissue damage in experimentally induced atopic dermatitis in mice. Cytokine 106, 45–53 (2018).
Binabaj, M. M. et al. EW-7197 prevents ulcerative colitis-associated fibrosis and inflammation. J. Cell Physiol. 234, 11654–11661 (2019).
Ko, H. K. et al. The role of transforming growth factor-β2 in cigarette smoke-induced lung inflammation and injury. Life Sci. 320, 121539 (2023).
Waghabi, M. C. et al. Pharmacological inhibition of transforming growth factor beta signaling decreases infection and prevents heart damage in acute Chagas’ disease. Antimicrob. Agents Chemother. 53, 4694–4701 (2009).
Waghabi, M. C. et al. SB-431542, a transforming growth factor beta inhibitor, impairs Trypanosoma cruzi infection in cardiomyocytes and parasite cycle completion. Antimicrob. Agents Chemother. 51, 2905–2910 (2007).
Mezger, M. C. et al. Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression. Viruses 14, 1308 (2022).
Xiao, Y. Q., Liu, K., Shen, J. F., Xu, G. T. & Ye, W. SB-431542 inhibition of scar formation after filtration surgery and its potential mechanism. Invest Ophthalmol. Vis. Sci. 50, 1698–1706 (2009).
Hasegawa, T., Nakao, A., Sumiyoshi, K., Tsuchihashi, H. & Ogawa, H. SB-431542 inhibits TGF-beta-induced contraction of collagen gel by normal and keloid fibroblasts. J. Dermatol Sci. 39, 33–38 (2005).
Soleimani, A. et al. Novel oral transforming growth factor-β signaling inhibitor potently inhibits postsurgical adhesion band formation. J. Cell Physiol. 235, 1349–1357 (2020).
Monteleone, G. et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol. Ther. 20, 870–876 (2012).
Monteleone, G. et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N. Engl. J. Med 372, 1104–1113 (2015).
Sands, B. E. et al. Mongersen (GED-0301) for Active Crohn’s Disease: Results of a Phase 3 Study. Am. J. Gastroenterol. 115, 738–745 (2020).
Huo, D., Bi, X. Y., Zeng, J. L., Dai, D. M. & Dong, X. L. Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion. Mol. Cell Biochem. https://doi.org/10.1007/s11010-023-04912-y (2023).
Zhang, C. et al. Mitomycin C induces pulmonary vascular endothelial-to-mesenchymal transition and pulmonary veno-occlusive disease via Smad3-dependent pathway in rats. Br. J. Pharm. 178, 217–235 (2021).
Meng, J. et al. Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice. Mol. Ther. Methods Clin. Dev. 18, 791–802 (2020).
Liu, S. et al. Suppression of TGFβR-Smad3 pathway alleviates the syrinx induced by syringomyelia. Cell Biosci. 13, 98 (2023).
Ji, X. et al. Specific Inhibitor of Smad3 (SIS3) Attenuates Fibrosis, Apoptosis, and Inflammation in Unilateral Ureteral Obstruction Kidneys by Inhibition of Transforming Growth Factor β (TGF-β)/Smad3 Signaling. Med Sci. Monit. 24, 1633–1641 (2018).
Zhang, Y., Meng, X. M., Huang, X. R. & Lan, H. Y. The preventive and therapeutic implication for renal fibrosis by targetting TGF-β/Smad3 signaling. Clin. Sci. (Lond.) 132, 1403–1415 (2018).
Pan, W. et al. SIS3 suppresses osteoclastogenesis and ameliorates bone loss in ovariectomized mice by modulating Nox4-dependent reactive oxygen species. Biochem Pharm. 195, 114846 (2022).
Shou, J. et al. SIS3, a specific inhibitor of smad3, attenuates bleomycin-induced pulmonary fibrosis in mice. Biochem Biophys. Res Commun. 503, 757–762 (2018).
Rudnik, M. et al. Elevated Fibronectin Levels in Profibrotic CD14(+) Monocytes and CD14(+) Macrophages in Systemic Sclerosis. Front Immunol. 12, 642891 (2021).
Xiang, W. et al. Inhibition of SMAD3 effectively reduces ADAMTS-5 expression in the early stages of osteoarthritis. BMC Musculoskelet. Disord. 24, 130 (2023).
He, H. et al. Treatment for type 2 diabetes and diabetic nephropathy by targeting Smad3 signaling. Int J. Biol. Sci. 20, 200–217 (2024).
He, H. et al. Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ. Int J. Mol. Sci. 24, 11396 (2023).
Wu, C. P. et al. SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Lett. 433, 259–272 (2018).
Chihara, Y. et al. A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells. Breast Cancer Res Treat. 166, 55–68 (2017).
Conidi, A., van den Berghe, V. & Huylebroeck, D. Aptamers and their potential to selectively target aspects of EGF, Wnt/beta-catenin and TGFbeta-smad family signaling. Int J. Mol. Sci. 14, 6690–6719 (2013).
Lim, S. K. & Hoffmann, F. M. Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling. Proc. Natl Acad. Sci. USA 103, 18580–18585 (2006).
Zhao, B. M. & Hoffmann, F. M. Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol. Biol. Cell 17, 3819–3831 (2006).
Huang, C. et al. Expression, purification, and functional characterization of recombinant PTD-SARA. Acta Biochim Biophys. Sin. (Shanghai) 43, 110–117 (2011).
Ji, W. P. & Dong, Y. Targeting Yes-associated Protein with Evolved Peptide Aptamers to Disrupt TGF-beta Signaling Pathway: Therapeutic Implication for Bone Tumor. Mol. Inf. 34, 771–777 (2015).
Cheifetz, S. et al. Heterodimeric transforming growth factor beta. Biological properties and interaction with three types of cell surface receptors. J. Biol. Chem. 263, 10783–10789 (1988).
Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. Embo j. 21, 1743–1753 (2002).
van den Bosch, M. H. et al. Canonical Wnt signaling skews TGF-β signaling in chondrocytes towards signaling via ALK1 and Smad 1/5/8. Cell Signal 26, 951–958 (2014).
Pannu, J., Nakerakanti, S., Smith, E., ten Dijke, P. & Trojanowska, M. Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J. Biol. Chem. 282, 10405–10413 (2007).
Bharathy, S., Xie, W., Yingling, J. M. & Reiss, M. Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res 68, 1656–1666 (2008).
Daly, A. C., Randall, R. A. & Hill, C. S. Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol. Cell Biol. 28, 6889–6902 (2008).
Hussein, Y. M., Mohamed, R. H., El-Shahawy, E. E. & Alzahrani, S. S. Interaction between TGF-β1 (869C/T) polymorphism and biochemical risk factor for prediction of disease progression in rheumatoid arthritis. Gene 536, 393–397 (2014).
Nakao, E. et al. Elevated Plasma Transforming Growth Factor β1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study. Am. J. Hypertens. 30, 808–814 (2017).
Kanzler, S. et al. Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta. J. Viral Hepat. 8, 430–437 (2001).
Wei, Y., Tian, Q., Zhao, X. & Wang, X. Serum transforming growth factor beta 3 predicts future development of nonalcoholic fatty liver disease. Int J. Clin. Exp. Med 8, 4545–4550 (2015).
Wu, C. Y., Li, L. & Zhang, L. H. Detection of serum MCP-1 and TGF-β1 in polymyositis/dermatomyositis patients and its significance. Eur. J. Med Res 24, 12 (2019).
Boix, F. et al. A high concentration of TGF-β correlates with opportunistic infection in liver and kidney transplantation. Hum. Immunol. 82, 414–421 (2021).
Leppäpuska, I. M. et al. Low TGF-β1 in Wound Exudate Predicts Surgical Site Infection After Axillary Lymph Node Dissection. J. Surg. Res 267, 302–308 (2021).
Capuano, A. et al. Hepatocyte growth factor and transforming growth factor beta1 ratio at baseline can predict early response to cyclophosphamide in systemic lupus erythematosus nephritis. Arthritis Rheum. 54, 3633–3639 (2006).
Daïen, C. I. et al. TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis. Jt. Bone Spine 79, 471–475 (2012).
Sambuelli, A. et al. Serum transforming growth factor-beta1 levels increase in response to successful anti-inflammatory therapy in ulcerative colitis. Aliment Pharm. Ther. 14, 1443–1449 (2000).
Rodrigues-Junior, D. M. et al. Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma. Carcinogenesis 40, 1452–1461 (2019).
Scarpa, M. et al. TGF-beta1 and IGF-1 production and recurrence of Crohn’s disease after ileo-colonic resection. J. Surg. Res 152, 26–34 (2009).
Scarpa, M. et al. TGF-beta1 and IGF-1 and anastomotic recurrence of Crohn’s disease after ileo-colonic resection. J. Gastrointest. Surg. 12, 1981–1990 (2008).
Memon, A. A. et al. Transforming growth factor (TGF)-β levels and unprovoked recurrent venous thromboembolism. J. Thromb. Thrombolysis 38, 348–354 (2014).
Mattey, D. L., Nixon, N., Dawes, P. T. & Kerr, J. Association of polymorphism in the transforming growth factor {beta}1 gene with disease outcome and mortality in rheumatoid arthritis. Ann. Rheum. Dis. 64, 1190–1194 (2005).
Watanabe, Y. et al. Transforming Growth Factor-β1 as a Predictor for the Development of Hepatocellular Carcinoma: A Nested Case-Controlled Study. EBioMedicine 12, 68–71 (2016).
Ikeguchi, M., Iwamoto, A., Taniguchi, K., Katano, K. & Hirooka, Y. The gene expression level of transforming growth factor-beta (TGF-beta) as a biological prognostic marker of hepatocellular carcinoma. J. Exp. Clin. Cancer Res 24, 415–421 (2005).
Wu, X. et al. Development of a TGF-β signaling-related genes signature to predict clinical prognosis and immunotherapy responses in clear cell renal cell carcinoma. Front Oncol. 13, 1124080 (2023).
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This work was supported by the National Key R&D Program of China (2021YFF1201303), the Beijing Natural Science Foundation (BJNSF) (7242119), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-012).
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J.H. supervised the project. J.H., C.L., and T.F. conceived the idea. Z.D., T.F., and C.L. drafted the manuscript. Z.D., C.X., H.T., and Y.Z. polished the language. All authors read and approved the final manuscript.
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Deng, Z., Fan, T., Xiao, C. et al. TGF-β signaling in health, disease and therapeutics. Sig Transduct Target Ther 9, 61 (2024). https://doi.org/10.1038/s41392-024-01764-w
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DOI: https://doi.org/10.1038/s41392-024-01764-w
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