Abstract
Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in cholesterol- and sphingolipid-enriched domains. Flotillin heterotetramers can assemble into large oligomers to form molecular scaffolds that regulate the clustering of at the plasma membrane and activity of several receptors. Moreover, flotillins are upregulated in many invasive carcinomas and also in sarcoma, and this is associated with poor prognosis and metastasis formation. When upregulated, flotillins promote plasma membrane invagination and induce an endocytic pathway that allows the targeting of cargo proteins in the late endosomal compartment in which flotillins accumulate. These late endosomes are not degradative, and participate in the recycling and secretion of protein cargos. The cargos of this Upregulated Flotillin–Induced Trafficking (UFIT) pathway include molecules involved in signaling, adhesion, and extracellular matrix remodeling, thus favoring the acquisition of an invasive cellular behavior leading to metastasis formation. Thus, flotillin presence from the plasma membrane to the late endosomal compartment influences the activity, and even modifies the trafficking and fate of key protein cargos, favoring the development of diseases, for instance tumors. This review summarizes the current knowledge on flotillins and their role in cancer development focusing on their function in cellular membrane remodeling and vesicular trafficking regulation.
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1 Membrane domains
Membrane micro-domains, also called “lipid rafts,” are highly ordered membrane subdomains enriched in cholesterol, sphingolipids, and gangliosides and with roles in membrane organization, lateral movement and trafficking of molecules, and signal transduction. Several signal transduction processes involved in cell adhesion and migration and in the formation of sorting platforms for targeted protein trafficking are dependent on this precise membrane organization. The first evidence of the presence of heterogeneous domains in the cell membrane came from biochemical studies based on their insolubility in non-ionic detergent at low temperature and their isolation by flotation in sucrose gradient, hence their name detergent-resistant membrane (DRM) domains. Although their in vivo presence was unclear at that time, new technologies, particularly super-resolution imaging and spectroscopy techniques and lipid analysis, provided data to better define these “lipid rafts” as heterogeneous and highly dynamic domains that range from 10 to 300 nm in size. Lipid-lipid and protein-lipid interactions and clustering allow the formation of these heterogeneous membrane domains that dynamically tune the bioactivity of cell membranes [1, 2].
These membrane domains have crucial roles in the regulation of adhesion, cell signaling pathways, protein sorting, and trafficking, all key processes in cancer development. Thus, alterations in membrane domain homeostasis (at the lipid and/or protein level) may directly promote changes in these processes, leading to tumorigenesis.
Flotillin 1 and flotillin 2, when overexpressed, might perturb membrane domain homeostasis during tumorigenesis. In the last years, our vision of flotillin role has drastically evolved. Several convincing studies in cellular models have demonstrated the role of flotillins in the establishment of protein complexes at the plasma membrane and in endocytosis; however, flotillin-deficient mice are viable and fertile [3, 4]. Some insights came from the observation that flotillins are upregulated in major human pathologies, particularly in many tumors where their overexpression correlates with poor prognosis (Table 1). Consistently, flotillin co-upregulation in various cellular models promotes cell invasion and metastasis [5,6,7,8,9,10,11], and flotillin 2 knockout mice allowed demonstrating the crucial role of flotillins in metastasis formation [12]. This led to the notion of gain-of-function effect of flotillins when they are upregulated. Indeed, upregulated flotillins promote plasma membrane invagination and endocytosis towards late endosomes, thus modifying the trafficking of different cargos. Therefore, the Upregulated Flotillin–Induced Trafficking (UFIT) pathway changes cell fate and promotes tumorigenesis.
2 Flotillins
Flotillins were concomitantly discovered by two different groups as proteins upregulated in mammalian retinal ganglion cells upon optic nerve injury (hence their name Reggie) [36] and as markers of lipid raft domains in plasma membrane extracts from mouse lung tissue (hence their name flotillins) [37].
Flotillin-like proteins are found in several organisms such as bacteria, the social amoeba Dictyostelium discoideum, fungi, and plants, but are absent in Caenorhabditis elegans and budding yeast. In all these organisms, flotillins were found in DRM, when tested. In bacteria, flotillins are present in DRM domains and can be visualized as discrete membrane regions by fluorescent microscopy. Bacterial flotillins regulate membrane fluidity, act as scaffold proteins for efficient protein complex assembly, and participate in the formation of structures that promote membrane fusion and invagination during cell division and sporulation [38]. In Dictyostelium discoideum, three flotillin-like proteins, VacA, VacB, and VacC, are associated with membrane domains and participate in particle uptake, plasma membrane recycling, and phagolysosome biogenesis [39]. In various plant genomes, flotillin homologs were identified. For instance, in Arabidopsis thaliana, there are three homologs that are detected in plasma membrane DRM [40].
Flotillins are composed of two domains (Fig. 1a): the N-terminal SPFH (stomatin, prohibitin, flotillin, HflK/C) domain associated with the inner leaflet of cell membranes and the C-terminal flotillin domain that is found only in flotillins 1 and 2 and is responsible for flotillin oligomerization [41, 42]. Although flotillins can form homo-tetramers, flotillin hetero-oligomers (composed of two flotillin 1 and two flotillin 2) are the predominant form. Flotillin hetero-oligomers assemble into large oligomers that form flotillin platforms at the membrane [42] (Fig. 1b). Micro-domains formed by oligomerized flotillins are distinct from those scaffolded by caveolins. Flotillins are interdependent regarding their functions and stability. Indeed, the decreased expression of one flotillin results in the reduced expression also of the other [4, 43,44,45,46].
The SPFH domain allows the association of flotillins with cholesterol-rich membrane domains via interaction with the hydrophobic amino acid stretches or with putative CRAC (cholesterol recognition amino acid consensus) motifs and through post-translational modifications (palmitoylation for flotillin 1, and both palmitoylation and myristoylation for flotillin 2) [47]. The SPFH domain of flotillin 2 can bind to actin, and this interaction stabilizes flotillin domains. Indeed, actin depolymerization increases their mobility [48,49,50]. Flotillins are mainly localized in membrane compartments, such as the plasma membrane, the endoplasmic reticulum (ER), the Golgi apparatus, and a variety of late endosomal compartments, characterized as endolysosomes, phagosomes, or multi-vesicular endosomes, depending on the cellular model analyzed [9, 45, 51, 52]. Whether flotillins are transported from the ER directly to the plasma membrane or whether they pass through intermediate compartments is unknown. The secretion pathway of flotillin 1 is apparently unconventional (i.e., Golgi-independent) [41]. Flotillin 1 palmitoylation at Cys34 is required for its exit from the ER and its localization at the plasma membrane [41, 53, 54]. Some data obtained in HeLa cells incubated with brefeldin A, to inhibit transport from the Golgi apparatus, suggest that flotillin 2 could use the conventional secretory pathway [45]. The presence of flotillins 1 and 2 in the Golgi apparatus was also confirmed in experiments where proteins present in Golgi-derived detergent-insoluble complexes were sequenced and by immuno-electron microscopy showing flotillin 2 in Golgi vesicles but not in Golgi stacks [41, 45, 55]. Moreover, the expression of truncated flotillins 1 and 2 bearing only their SPFH domains results in their retention in the Golgi, but this is not observed with the full-length proteins. Post-translational modifications could also influence flotillin distribution. Interestingly, non-palmitoylable flotillin 1 appears to be more prone to sumoylation, a post-translational modification that promotes flotillin 1 nuclear translocation [56]. The expression level of flotillins also has a strong impact on their cellular distribution (Fig. 1c). At low expression levels, flotillins mainly reside at the inner leaflet of the plasma membrane, whereas they accumulate in late endosomes when upregulated, for example in tumor cells [9]. Flotillin redistribution from the plasma membrane to late endosomes is induced also by incubation with EGF [57, 58]. In HeLa cells, this effect involves dynamin [59]. It has been suggested that Fyn-dependent phosphorylation of flotillin 1 (Y160) and flotillin 2 (Y163) induces their endocytosis. Moreover, these phosphorylatable residues appear to be important for flotillin hetero-oligomerization and their subsequent endocytosis [46]. As flotillin upregulation favors their oligomerization, it will be interesting to analyze whether this affects also Fyn activation. Recently, it was shown that the use of ultrasound in combination with microbubbles, a strategy for targeted intracellular delivery of molecules, elicits a signaling pathway involving Fyn and the palmitoyl transferase DHHC5, which in turn triggers an increase in flotillin internalization [60].
3 Flotillin role in tumorigenesis
Flotillins are upregulated in a subset of all carcinomas and also in sarcomas, and this is associated with poor patient prognosis (see Table 1 for an up-to-date census).
In the last years, some studies have started to identify how flotillins are upregulated in cancer. Not surprisingly, flotillin expression is regulated through mechanisms that are perturbed in tumor cells. Indeed, flotillin upregulation might be caused by microRNA downregulation in tumors (Table 2). For instance, microRNA-802 is downregulated in breast, pancreatic, and prostate cancers. In prostate cancer, this microRNA controls the expression of genes associated with epithelial to mesenchymal transition (EMT) and directly targets flotillin 2 [61]. Flotillin 1 is a microRNA-124 target in breast tumors [16], and flotillin 2 is a microRNA-485-5p target in non-small-cell lung cancer [62]. In gastric cancer, microRNA-485-5p targets flotillin 1 and microRNA-449a flotillin 2 [63, 64]. Gene amplification also might increase flotillin expression level. Specifically, in breast and gastric cancers, flotillin 2 is co-amplified with ERBB2 (these two genes are close on chromosome 17) [13, 22]. At the transcriptional level, flotillin 2 is a direct target of TAp73β and TAp63γ, two p53 family members [65]. Moreover, signaling leading to activation of the mitogen-activated kinase (MAPK)/ERK pathway, such as growth factor receptor activation, or of transcription factors, such as serum response factor (SRF), early growth response gene 1 (EGR1), and also retinoic acid receptor (RAR) and PPAR, could participate in flotillin upregulation [66]. As these signaling pathways and transcription factors are often activated upon oncogenic stimulation, this could explain why flotillin upregulation occurs in so many different cancers. In addition, flotillin 1 expression is increased upon H-Ras expression in MCF10A mammary cells to increase tumor aggressiveness [7]. Moreover, in condition of suboptimal cancer treatment, metastasis formation is enhanced, as reported for small-size hepatocellular carcinoma with insufficient radiofrequency ablation. When hepatocellular carcinoma cells are heat-treated to mimic this process, flotillin upregulation is observed [67].
Until now, no animal models mimicking flotillin upregulation were generated, except in Drosophila, where flotillin overexpression mutants showed perturbed adhesion molecule and morphogen distribution [76]. Moreover, flotillin upregulation in cellular models devoid of oncogenic pathway activation is sufficient to promote extracellular matrix (ECM) degradation, cell migration, and cell invasion [9]. This suggests that flotillin expression level is a crucial element in their function.
It is important to note that most of the studies on flotillins were carried out in tumor cell lines where flotillin expression levels are greatly increased. This implies that the majority of cellular functions attributed to flotillins since their discoveries were identified in a context of overexpression that favors their oligomerization, leading to plasma membrane remodeling and endocytosis. Moreover, at the molecular level, the functions of flotillins are usually associated with their local accumulation that is influenced by their expression level. This is the case for their role in cell signaling. Specifically, flotillins form membrane micro-domains where different receptors and proteins concentrate. As these regions act as signaling platforms, flotillins are associated with the regulation of different signaling processes. Similarly, most of the experiments that demonstrated flotillin function in endocytosis were performed in conditions of increased flotillin local concentration (after flotillin transfection and therefore overexpression). These experiments showed that the UFIT pathway is responsible for the endocytosis of several proteins towards flotillin-positive late endosomes, where their activity is modified and from where the cargos could be exocytosed and recycled at the cell surface in order to participate in tumorigenesis. Endocytic recycling and signaling are two intertwining processes of which flotillins emerge as key regulators.
3.1 Flotillin-mediated endocytosis, a vesicular trafficking pathway exacerbated in cancer
As flotillins are present in the plasma membrane and in purified endosomes, Nichols’ group wanted to determine their role during endocytosis and showed that flotillins are found in endocytic vesicles, which are distinct from clathrin-coated pits and caveolae, and are involved in the internalization of protein cargos, such as the glycophosphatidylinositol (GPI)-anchor protein CD59 and the ganglioside GM1 [43, 77]. Moreover, pioneering studies revealed that overexpression of both flotillins induces flotillin hetero-oligomers that generate flotillin-positive plasma membrane micro-domains promoting plasma membrane curvature and the formation of endocytic vesicles [43]. Increasing the size of flotillin oligomers in HeLa cells, especially by incubation with epidermal growth factor, led also to their endocytosis from the plasma membrane [46]. Altogether, these studies carried out more than ten years ago suggested the involvement of flotillin micro-domains in endocytosis.
Since then, other protein cargos the UFIT pathway were identified, such as transmembrane and GPI-anchor proteins [9, 78,79,80,81,82,83,84] and extracellular proteins [85, 86] (Table 3). Most of them can enter into the cell through clathrin-mediated endocytosis or other clathrin-independent pathways, such as macro-pinocytosis. What orients the choice between flotillin-dependent or flotillin-independent endocytic pathways is not known, but the binding of a ligand could be an important parameter for transmembrane proteins. For example, the low-density lipoprotein receptor–related protein 6 (LRP6) is internalized by different endocytic routes, depending on ligand binding. In the presence of the ligand, LRP6 is endocytosed via a clathrin-dependent route that results in LRP6 trafficking to the lysosome for its degradation. Conversely, in the absence of ligand, LRP6 is endocytosed in a flotillin-dependent manner [84]. The choice of the flotillin-mediated endocytosis pathway for a given cargo could be explained by its presence in flotillin-rich membrane micro-domains, as shown using super-resolution microscopy for MT1-MMP [9], where the cargo can directly or indirectly interact with flotillins. Despite all these studies suggesting the existence of a flotillin-dependent endocytic pathway, its biological relevance and physiological relevance are challenged. Indeed, flotillin knockdown affects the clustering of several proteins at the plasma membrane, but their endocytosis is not totally impaired, probably because these protein cargos can also use other endocytic pathways. In addition, the absence of a marked phenotype in flotillin knockout mice that are viable and fertile [3, 4] does not argue in favor of an essential role of flotillins in endocytosis.
As previously mentioned, the involvement of flotillin in endocytosis initially emerged through approaches using artificial ectopic overexpression [43, 77]. As many publications showed that flotillin upregulation is a common feature of many invasive tumors, the relevance of flotillin-mediated endocytosis has regained interest recently. Unlike the moderate effect of flotillin loss of function, flotillin upregulation (gain of function) is harmful for tissue homeostasis because flotillin overexpression participates in tumor development and in Drosophila it disrupt intercellular adhesion, thus leading to embryonic lethality [76]. It will therefore be interesting to develop animal models in which flotillins can be upregulated in an inducible way to address in vivo the effect of their aberrant expression. One consequence of the UFIT pathway is the accumulation of flotillin-positive intracellular vesicles in the late endosomal compartment, particularly in endolysosomes [9, 57]. Currently, the role of flotillins in these intracellular vesicles is poorly described.
The molecular mechanisms of the UFIT pathway are not known. Local accumulation of flotillins at the plasma membrane is associated with the formation of invaginations [43]. Different proteins with properties similar to flotillins (i.e., membrane localization, oligomerization, actin binding) can bend membranes after their local accumulation [91]. Therefore, a local increase of flotillin concentration could be sufficient to induce membrane curvature and endocytosis. Experiments using optogenetics to force flotillin oligomerization to mimic this local concentration increase or in vitro approaches with artificial membranes in which flotillins are incorporated will allow validating such hypotheses. One can also imagine that flotillins can bend the membranes by recruiting different partners. This binding could be the direct results of the increased flotillin local concentration and/or of the generation of specific lipid domains. Indeed, flotillins affect sphingolipid distribution in membrane micro-domains. Specifically, flotillins bind to sphingosines through their SPFH region, and in the absence of flotillins, sphingosines in membrane micro-domains are impaired as well as the generation of sphingosine-1-phosphate [92]. Sphingosine-1-phosphate levels at the plasma membrane are associated with the formation of endocytic structures [93] and with the recruitment of Bin-Amphiphysin-Rvs (BAR) domain-containing endophilin A2 and B1 [94]. Interestingly, it was shown that endophilin A2 controls clathrin-independent endocytosis [95]. Other BAR domain–containing proteins, such as SNX, would be good candidate regulators of endocytosis promoted by flotillins because these proteins can bend the membranes and because flotillins are direct partners of SNX4 [96], a BAR domain protein that has already been implicated in endocytic mechanisms [97]. Some studies also suggested that flotillins participate in the recruitment of the clathrin-dependent endocytosis machinery. Indeed, amyloid precursor protein internalization requires the presence of flotillins and the recruitment of the AP2 adapter and clathrin, suggesting a mixed pathway [83]. Nevertheless, highly organized electron-dense clathrin-like coats were not detected at sites of plasma membrane invaginations in cells with upregulated flotillins. Similarly, the importance of dynamin in this process is unclear. Indeed, flotillin-mediated internalization of CTX-B [77] and Semaphorin 3A [85] but not of GPI-anchor proteins [78] seems to be independent of dynamin presence. Thus, depending on the cellular context and the cargos, different endocytic mechanisms of the UFIT pathway have been proposed. The identification of the mechanisms and machinery used to promote endocytic vesicle formation in the context of flotillin upregulation should be facilitated by the development of systems to force flotillin oligomerization without activation of additional signaling pathways.
3.2 Flotillin role in the late endocytic compartment: the example of MT1-MMP
Upregulated (endogenous and ectopic) flotillins are preferentially found in intracellular vesicles defined as CD63-, RAB7-, and LAMP-1-positive late endosomes (Fig. 1d); however, their functions in this endocytic and recycling compartment are not very clear at the moment [9, 45, 51, 52, 54]. Late endosomes could maturate and fuse with lysosomes or be delivered to the cell periphery [98]. One key function of these non-degradative flotillin-positive late endosomes is to allow cargo recycling [9, 96]. This was clearly illustrated in the case of MT1-MMP, a membrane-tethered matrix metalloproteinase with a key role in the regulation of localized ECM breakdown [9]. Indeed, MT1-MMP is targeted to flotillin-rich late endosomes upon flotillin upregulation (Fig. 2a) to allow its recycling and delivery at degradation sites. When cells degrade the gelatin matrix, flotillin-positive vesicles are observed at degradation sites, called invadopodia and identified by TKS5 and F-actin, from which MT1-MMP is delivered to promote matrix degradation (Fig. 2b). Flotillin upregulation is associated with increased MT1-MMP exocytosis, leading to increased matrix degradation, a key process during tumor cell invasion (see model in Fig. 2c). Also, in a non-pathological context, flotillins are involved in invasion and especially in ECM degradation. Indeed, flotillin inhibition in macrophages induces a decrease in gelatin matrix degradation in 2D. In this model, through their interaction with the kinesin KIF9, flotillins appear to regulate the formation of ECM degradation structures [99]. Interestingly, kinesins are involved in MT1-MMP transport in tumor cells [100]. We can hypothesize that flotillin micro-domains serve as a membrane platform for KIF9 recruitment at vesicles, thus promoting the transport of metalloproteases. However, this possible function has not been thoroughly investigated yet.
In biochemical assays, flotillin 2, through its SPFH domain, binds to proteins involved in recycling pathways, such as Rab11 and SNX4; however, flotillin co-localization with these proteins has not often clearly observed in various cell types, even cancer cells with upregulated flotillins (see Fig. 1d for MDA-MB-231 cells) [9, 96]. How the UFIT pathway influences the activity and/or recruitment of these proteins along the endocytic pathway remains to be determined. Flotillins also bind to Hrs, a protein of the ESCRT-0 complex, and could affect Hrs-mediated cargo sorting to control their degradation [101]. Moreover, the ESCRT complex also has a role in protein trafficking from the late endosomal compartment to the plasma membrane [102]. Therefore, more studies on the role of flotillins in these late endosomes are needed to clarify their function in this compartment where they accumulate when upregulated, such as in cancer cells.
3.3 Flotillins and signaling
Several independent studies reported that flotillins influence the activation of signaling pathways that promote EMT, cellular adhesion perturbations, and cellular invasion. In these last years, the number of publications that identified a role for flotillins in the regulation of oncogenic signaling pathways has increased (Table 4). Many of these studies were performed by decreasing flotillin expression levels in tumor cells and demonstrated that flotillins are necessary for the activation of oncogenic signaling pathways. However, studying the consequences of flotillin upregulation, which is accompanied by a gain-of-function effect, is required particularly to determine whether their overexpression is sufficient to induce downstream effects. Indeed, recently, ectopic overexpression of flotillins is used again to analyze their functions. For example, in cellular models of lung adenocarcinoma, overexpression of flotillins is sufficient to strongly induce cell invasion [103]. Similarly, in models of hepatocellular carcinoma, overexpression of flotillins is sufficient to induce a Raf/MEK/ERK1/2-dependent signaling cascade. This leads to EMT activation and increased cell invasion in vitro and to metastasis formation in vivo [11]. Finally, in a model of nasopharyngeal carcinoma, overexpression of flotillins induces EMT and consequently increases cell migration and invasion [5, 29]. The molecular mechanism seems to depend on the secretion of TGF-β1 and activation of the TGF-β/SMAD3, PI3K/Akt3, and NF-κB signaling pathways. These examples are not exhaustive and every year new studies show that overexpression of flotillins is sufficient to acquire invasive properties in different cancer cell types (Table 4). All these studies that identified a key role of flotillins in signaling pathways involved in cancer development were performed using cancer cell lines with many mutations in genes with roles in tumor induction and invasion. Therefore, to specifically identify the precise contribution of flotillin upregulation in the activation of these key signaling pathways during tumor development, cellular models devoid of these mutations should be used in the future. Upregulation of flotillins in normal cells is sufficient to acquire invasive properties and promote their capacity to degrade the ECM [9]. It is important to emphasize that overexpressed flotillins can simultaneously activate several signaling pathways. Therefore, preventing/limiting flotillin upregulation could have a far superior therapeutic efficacy compared with approaches in which one single protein kinase or signaling pathway is inhibited.
The molecular mechanisms of activation of oncogenic pathways by the UFIT pathway remain poorly identified. Flotillins could have key functions at different cellular levels. First, flotillins at the plasma membrane participate in the clustering of membrane proteins, such as the receptor tyrosine kinases ErbB2 and EGFR involved in the activation of oncogenic signaling pathways [14, 108]. In neuroblastoma, flotillin 1 was identified from a screen as a phosphotyrosine-containing protein associated with the oncogenic anaplastic lymphoma kinase (ALK) and was shown to control ALK activity through its stabilization at the plasma membrane [10]. Moreover, when flotillins are upregulated, like in tumor cells, they accumulate in non-degradative late endosomes with cargos of the UFIT pathway such as MT1-MMP [9]. It is now important to determine the role of flotillins in late endosomes, particularly their contribution to the maintenance of the signaling pathways starting at the plasma membrane. Endocytosis contributes to downregulate incoming signals, but in some cases signaling pathways could be maintained in early and late endosomes [109]. Whether and how flotillins participate in the decision to degrade or not the endocytosed material remains to be determined. Interestingly, flotillin 1 directly interacts with Raf, MEK1/2, and ERK1/2 [108], but it is not known whether flotillins could regulate their recruitment to signaling endosomes.
Finally, post-translational modifications, such as phosphorylation and sumoylation, also could modify flotillin functions. For instance, it has been proposed that sumoylation of a non-palmitoylated form of flotillin 1 favors Snail stabilization and Snail-mediated EMT gene expression in prostate cancer cells [56].
In conclusion, flotillins emerged these last years as proteins that play a pivotal role in a broad spectrum of human cancers. For the future structure and function analysis of the flotillin-containing membrane domains at the nanoscale level in living cells, the use of high-resolution microscopy techniques, such as STED, SIM, PALM, and dSTORM, will be very useful. Combining these approaches with new lipid dyes will allow the precise identification of the properties of membrane micro-domains. Above all, the development of new tools and animal models to study flotillin upregulation in a temporal and spatial controlled manner is required to better understand their mechanism of action and their role in pathologies, such as cancer. Particularly, identifying the role of flotillins in the late endosomal recycling compartment and how the UFIT pathway influences the dynamic turnover and fate of different protein cargos will be an important step.
References
Lingwood, D., & Simons, K. (2010). Lipid rafts as a membrane-organizing principle. Science, 327, 46–50.
Sezgin, E., Levental, I., Mayor, S., & Eggeling, C. (2017). The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nature Reviews. Molecular Cell Biology, 18, 361–374.
Bitsikas, V., et al. (2014). The role of flotillins in regulating Aβ production, investigated using flotillin 1−/−, flotillin 2−/− double knockout mice. PLoS One, 9, e85217.
Ludwig, A., Otto, G. P., Riento, K., Hams, E., Fallon, P. G., & Nichols, B. J. (2010). Flotillin microdomains interact with the cortical cytoskeleton to control uropod formation and neutrophil recruitment. The Journal of Cell Biology, 191, 771–781.
Cao, S., Cui, Y., Xiao, H., Mai, M., Wang, C., Xie, S., Yang, J., Wu, S., Li, J., Song, L., Guo, X., & Lin, C. (2016). Upregulation of flotillin-1 promotes invasion and metastasis by activating TGF-β signaling in nasopharyngeal carcinoma. Oncotarget, 7, 4252–4264.
Hazarika, P., McCarty, M., Prieto, V. G., George, S., Babu, D., Koul, D., Bar-Eli, M., & Duvic, M. (2004). Up-regulation of flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1. Cancer Research, 64, 7361–7369.
Koh, M., Yong, H. Y., Kim, E. S., Son, H., Jeon, Y. R., Hwang, J. S., Kim, M. O., Cha, Y., Choi, W. S., Noh, D. Y., Lee, K. M., Kim, K. B., Lee, J. S., Kim, H. J., Kim, H., Kim, H. H., Kim, E. J., Park, S. Y., Kim, H. S., Moon, W. K., Choi Kim, H. R., & Moon, A. (2016). A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness: flotillin-1 is important for breast cancer aggressiveness. International Journal of Cancer, 138, 1232–1245.
Liu, J., et al. (2015). Flotillin-2 promotes metastasis of nasopharyngeal carcinoma by activating NF-kappaB and PI3K/Akt3 signaling pathways. Scientific Reports, 5, 11614.
Planchon, D., et al. (2018). MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins. Journal of Cell Science, 131, jcs218925.
Tomiyama, A., Uekita, T., Kamata, R., Sasaki, K., Takita, J., Ohira, M., Nakagawara, A., Kitanaka, C., Mori, K., Yamaguchi, H., & Sakai, R. (2014). Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association. Cancer Research, 74, 3790–3801.
Wang, C.-H., Zhu, X. D., Ma, D. N., Sun, H. C., Gao, D. M., Zhang, N., Qin, C. D., Zhang, Y. Y., Ye, B. G., Cai, H., Shi, W. K., Cao, M. Q., & Tang, Z. Y. (2017). Flot2 promotes tumor growth and metastasis through modulating cell cycle and inducing epithelial-mesenchymal transition of hepatocellular carcinoma. American Journal of Cancer Research, 7, 1068–1083.
Berger, T., Ueda, T., Arpaia, E., Chio, I. I., Shirdel, E. A., Jurisica, I., Hamada, K., You-ten, A., Haight, J., Wakeham, A., Cheung, C. C., & Mak, T. W. (2013). Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model. Oncogene, 32, 4989–4994.
Perou, C. M., Sørlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., Rees, C. A., Pollack, J. R., Ross, D. T., Johnsen, H., Akslen, L. A., Fluge, O., Pergamenschikov, A., Williams, C., Zhu, S. X., Lønning, P. E., Børresen-Dale, A. L., Brown, P. O., & Botstein, D. (2000). Molecular portraits of human breast tumours. Nature, 406, 747–752.
Pust, S., Klokk, T. I., Musa, N., Jenstad, M., Risberg, B., Erikstein, B., Tcatchoff, L., Liestøl, K., Danielsen, H. E., van Deurs, B., & Sandvig, K. (2013). Flotillins as regulators of ErbB2 levels in breast cancer. Oncogene, 32, 3443–3451.
Wang, X., et al. (2013). Flotillin-2 is associated with breast cancer progression and poor survival outcomes. Journal of Translational Medicine, 11, 190.
Li, L., et al. (2013). Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Molecular Cancer, 12, 163.
Liu, Y., Lin, L., Huang, Z., Ji, B., Mei, S., Lin, Y., & Shen, Z. (2015). High expression of flotillin-2 is associated with poor clinical survival in cervical carcinoma. International Journal of Clinical and Experimental Pathology, 8, 622–628.
Li, Z., Yang, Y., Gao, Y., Wu, X., Yang, X., Zhu, Y., Yang, H., Wu, L., Yang, C., & Song, L. (2016). Elevated expression of flotillin-1 is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer. American Journal of Cancer Research, 6, 38–50.
Baig, N., et al. (2019). Clinical significance and comparison of flotillin 1 expression in left and right colon cancer. Oncology Letters. https://doi.org/10.3892/ol.2019.10401.
Li, T., et al. (2019). FLOT2 overexpression is associated with the progression and prognosis of human colorectal cancer. Oncology Letters. https://doi.org/10.3892/ol.2019.9882.
Song, L., et al. (2012). Flotillin-1 promotes tumor necrosis factor-α receptor signaling and activation of NF-κB in esophageal squamous cell carcinoma cells. Gastroenterology, 143, 995–1005.e12.
Zhu, Z., et al. (2013). Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. PLoS One, 8, e62365.
Rickman, D. S., Millon, R., de Reynies, A., Thomas, E., Wasylyk, C., Muller, D., Abecassis, J., & Wasylyk, B. (2008). Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene, 27, 6607–6622.
Zhang, S. H., et al. (2013). High expression of FLOT1 is associated with progression and poor prognosis in hepatocellular carcinoma. PLoS One, 8, e64709.
Zhang, P.-F., Zeng, G. Q., Hu, R., Li, C., Yi, H., Li, M. Y., Li, X. H., Qu, J. Q., Wan, X. X., He, Q. Y., Li, J. H., Chen, Y., Ye, X., Li, J. Y., Wang, Y. Y., Feng, X. P., & Xiao, Z. Q. (2012). Identification of Flotillin-1 as a novel biomarker for lymph node metastasis and prognosis of lung adenocarcinoma by quantitative plasma membrane proteome analysis. Journal of Proteomics, 77, 202–214.
Wang, Y.-L., Yao, W. J., Guo, L., Xi, H. F., Li, S. Y., & Wang, Z. M. (2015). Expression of flotillin-2 in human non-small cell lung cancer and its correlation with tumor progression and patient survival. International Journal of Clinical and Experimental Pathology, 8, 601–607.
Wen, Q., et al. (2015). Flot-2 expression correlates with EGFR levels and poor prognosis in surgically resected non-small cell lung cancer. PLoS One, 10, e0132190.
Doherty, S. D., et al. (2006). High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma. Melanoma Research, 16, 461–463.
Zhao, L., Lin, L., Pan, C., Shi, M., Liao, Y., Bin, J., & Liao, W. (2015). Flotillin-2 promotes nasopharyngeal carcinoma metastasis and is necessary for the epithelial-mesenchymal transition induced by transforming growth factor-&beta. Oncotarget, 6, 9781–9793.
Li, H., Zhang, Y., Chen, S. W., Li, F. J., Zhuang, S. M., Wang, L. P., Zhang, J., & Song, M. (2014). Prognostic significance of Flotillin1 expression in clinically N0 tongue squamous cell cancer. International Journal of Clinical and Experimental Pathology, 7, 996–1003.
Wen, Q., Alnemah, M. M., Luo, J., Wang, W., Chu, S., Chen, L., Li, J., Xu, L., Li, M., Zhou, J., & Fan, S. (2015). FLOT-2 is an independent prognostic marker in oral squamous cell carcinoma. International Journal of Clinical and Experimental Pathology, 8, 8236–8243.
Yan, Y., Yang, F. Q., Zhang, H. M., Che, J., & Zheng, J. H. (2014). Up-regulation of flotillin-2 is associated with renal cell carcinoma progression. Tumor Biology, 35, 10479–10486.
Zhang, Y., Li, J., Song, Y., Chen, F., Pei, Y., & Yao, F. (2014). Flotillin-1 expression in human clear-cell renal cell carcinoma is associated with cancer progression and poor patient survival. Molecular Medicine Reports, 10, 860–866.
Arkhipova, K. A., et al. (2014). Simultaneous expression of flotillin-1, flotillin-2, stomatin and caveolin-1 in non-small cell lung cancer and soft tissue sarcomas. BMC Cancer, 14, 100.
Huang, S., et al. (2019). Flot2 targeted by miR-449 acts as a prognostic biomarker in glioma. Artificial Cells, Blood Substitutes, and Biotechnology, 47, 250–255.
Schulte, T., Paschke, K. A., Laessing, U., Lottspeich, F., & Stuermer, C. A. (1997). Reggie-1 and reggie-2, two cell surface proteins expressed by retinal ganglion cells during axon regeneration. Development, 124, 577–587.
Bickel, P. E., Scherer, P. E., Schnitzer, J. E., Oh, P., Lisanti, M. P., & Lodish, H. F. (1997). Flotillin and epidermal surface antigen define a new family of caveolae-associated integral membrane proteins. The Journal of Biological Chemistry, 272, 13793–13802.
Lopez, D., & Koch, G. (2017). Exploring functional membrane microdomains in bacteria: an overview. Current Opinion in Microbiology, 36, 76–84.
Bosmani, C., et al. (2019). Flotillin homologues are essential for phagocytosis and participate in plasma membrane recycling and lysosome biogenesis. bioRxiv. https://doi.org/10.1101/582049.
Junková, P., et al. (2018). Mapping of plasma membrane proteins interacting with Arabidopsis thaliana flotillin 2. Frontiers in Plant Science, 9, 991.
Morrow, I. C., et al. (2002). Flotillin-1/reggie-2 traffics to surface raft domains via a novel golgi-independent pathway. Identification of a novel membrane targeting domain and a role for palmitoylation. The Journal of Biological Chemistry, 277, 48834–48841.
Solis, G. P., Hoegg, M., Munderloh, C., Schrock, Y., Malaga-Trillo, E., Rivera-Milla, E., & Stuermer, C. A. (2007). Reggie/flotillin proteins are organized into stable tetramers in membrane microdomains. The Biochemical Journal, 403, 313–322.
Frick, M., Bright, N. A., Riento, K., Bray, A., Merrified, C., & Nichols, B. J. (2007). Coassembly of flotillins induces formation of membrane microdomains, membrane curvature, and vesicle budding. Current Biology, 17, 1151–1156.
Guillaume, E., Comunale, F., Do Khoa, N., Planchon, D., Bodin, S., & Gauthier-Rouvière, C. (2013). Flotillin microdomains stabilize cadherins at cell-cell junctions. Journal of Cell Science, 126, 5293–5304.
Langhorst, M. F., Reuter, A., Jaeger, F. A., Wippich, F. M., Luxenhofer, G., Plattner, H., & Stuermer, C. A. (2008). Trafficking of the microdomain scaffolding protein reggie-1/flotillin-2. European Journal of Cell Biology, 87, 211–226.
Babuke, T., Ruonala, M., Meister, M., Amaddii, M., Genzler, C., Esposito, A., & Tikkanen, R. (2009). Hetero-oligomerization of reggie-1/flotillin-2 and reggie-2/flotillin-1 is required for their endocytosis. Cellular Signalling, 21, 1287–1297.
Neumann-Giesen, C., Falkenbach, B., Beicht, P., Claasen, S., Lüers, G., Stuermer, C. A., Herzog, V., & Tikkanen, R. (2004). Membrane and raft association of reggie-1/flotillin-2: role of myristoylation, palmitoylation and oligomerization and induction of filopodia by overexpression. The Biochemical Journal, 378, 509–518.
Langhorst, M. F., Solis, G. P., Hannbeck, S., Plattner, H., & Stuermer, C. A. (2007). Linking membrane microdomains to the cytoskeleton: regulation of the lateral mobility of reggie-1/flotillin-2 by interaction with actin. FEBS Letters, 581, 4697–4703.
Affentranger, S., et al. (2011). Dynamic reorganization of flotillins in chemokine-stimulated human T-lymphocytes. BMC Cell Biology, 12, 28.
Rossy, J., et al. (2009). Flotillins interact with PSGL-1 in neutrophils and, upon stimulation, rapidly organize into membrane domains subsequently accumulating in the uropod. PLoS One, 4, e5403.
Dermine, J. F., Duclos, S., Garin, J., St-Louis, F., Rea, S., Parton, R. G., & Desjardins, M. (2001). Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes. The Journal of Biological Chemistry, 276, 18507–18512.
Stuermer, C. A., Lang, D. M., Kirsch, F., Wiechers, M., Deininger, S. O., & Plattner, H. (2001). Glycosylphosphatidyl inositol-anchored proteins and fyn kinase assemble in noncaveolar plasma membrane microdomains defined by reggie-1 and -2. Molecular Biology of the Cell, 12, 3031–3045.
Jang, D., Kwon, H., Jeong, K., Lee, J., & Pak, Y. (2015). Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor. Journal of Cell Science, 128, 2179–2190.
Liu, J., Deyoung, S. M., Zhang, M., Dold, L. H., & Saltiel, A. R. (2005). The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. The Journal of Biological Chemistry, 280, 16125–16134.
Gkantiragas, I., Brügger, B., Stüven, E., Kaloyanova, D., Li, X. Y., Löhr, K., Lottspeich, F., Wieland, F. T., & Helms, J. B. (2001). Sphingomyelin-enriched microdomains at the Golgi complex. Molecular Biology of the Cell, 12, 1819–1833.
Jang, D., Kwon, H., Choi, M., Lee, J., & Pak, Y. (2019). Sumoylation of flotillin-1 promotes EMT in metastatic prostate cancer by suppressing Snail degradation. Oncogene, 38, 3248–3260.
Neumann-Giesen, C., Fernow, I., Amaddii, M., & Tikkanen, R. (2007). Role of EGF-induced tyrosine phosphorylation of reggie-1/flotillin-2 in cell spreading and signaling to the actin cytoskeleton. Journal of Cell Science, 120, 395–406.
Riento, K., Frick, M., Schafer, I., & Nichols, B. J. (2009). Endocytosis of flotillin-1 and flotillin-2 is regulated by Fyn kinase. Journal of Cell Science, 122, 912–918.
Meister, M., Zuk, A., & Tikkanen, R. (2014). Role of dynamin and clathrin in the cellular trafficking of flotillins. The FEBS Journal, 281, 2956–2976.
Fekri, F., et al. (2019). Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs. Scientific Reports, 9, 17768.
Wang, D., et al. (2017). MicroRNA-802 inhibits epithelial-mesenchymal transition through targeting Flotillin-2 in human prostate cancer. Bioscience Reports. https://doi.org/10.1042/BSR20160521.
Gao, F., Wu, H., Wang, R., Guo, Y., Zhang, Z., Wang, T., Zhang, G., Liu, C., & Liu, J. (2019). MicroRNA-485-5p suppresses the proliferation, migration and invasion of small cell lung cancer cells by targeting flotillin-2. Bioengineered, 10, 1–12.
Kang, M., Ren, M. P., Zhao, L., Li, C. P., & Deng, M. M. (2015). miR-485-5p acts as a negative regulator in gastric cancer progression by targeting flotillin-1. American Journal of Translational Research, 7, 2212–2222.
Li, Q., et al. (2015). miR-449a targets Flot2 and inhibits gastric cancer invasion by inhibiting TGF-β-mediated EMT. Diagnostic Pathology, 10, 202.
Sasaki, Y., Oshima, Y., Koyama, R., Maruyama, R., Akashi, H., Mita, H., Toyota, M., Shinomura, Y., Imai, K., & Tokino, T. (2008). Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members. Molecular Cancer Research, 6, 395–406.
Banning, A., et al. (2012). Transcriptional regulation of flotillins by the extracellularly regulated kinases and retinoid X receptor complexes. PLoS One, 7, e45514.
Zhang, N., Li, H., Qin, C., Ma, D., Zhao, Y., Zhu, W., & Wang, L. (2019). Insufficient radiofrequency ablation promotes the metastasis of residual hepatocellular carcinoma cells via upregulating flotillin proteins. Journal of Cancer Research and Clinical Oncology, 145, 895–907.
Liu, R., Xie, H., Luo, C., Chen, Z., Zhou, X., Xia, K., Chen, X., Zhou, M., Cao, P., Cao, K., & Zhou, J. (2015). Identification of FLOT2 as a novel target for microRNA-34a in melanoma. Journal of Cancer Research and Clinical Oncology, 141, 993–1006.
Butz, H., et al. (2015). miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. Oncotarget, 6, 12543–12557.
Wei, G., et al. (2018). miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2. Artificial Cells, Blood Substitutes, and Biotechnology, 46, 224–230.
Gong, H., Song, L., Lin, C., Liu, A., Lin, X., Wu, J., Li, M., & Li, J. (2013). Downregulation of miR-138 sustains NF- B activation and promotes lipid raft formation in esophageal squamous cell carcinoma. Clinical Cancer Research, 19, 1083–1093.
Xu, X., et al. (2014). Downregulation of microRNA-182-5p contributes to renal cell carcinoma proliferation via activating the AKT/FOXO3a signaling pathway. Molecular Cancer, 13, 109.
Mou, X., & Liu, S. (2016). MiR-485 inhibits metastasis and EMT of lung adenocarcinoma by targeting Flot2. Biochemical and Biophysical Research Communications, 477, 521–526.
Yang, F., et al. (2015). MiR-506 is down-regulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1. PLoS One, 10, e0120258.
Li, Y., et al. (2017). Lipid raft-mediated miR-3908 inhibition of migration of breast cancer cell line MCF-7 by regulating the interactions between AdipoR1 and Flotillin-1. World Journal of Surgical Oncology, 15, 69.
Hoehne, M., de Couet, H. G., Stuermer, C. A., & Fischbach, K. F. (2005). Loss- and gain-of-function analysis of the lipid raft proteins Reggie/Flotillin in Drosophila: they are posttranslationally regulated, and misexpression interferes with wing and eye development. Molecular and Cellular Neurosciences, 30, 326–338.
Glebov, O. O., Bright, N. A., & Nichols, B. J. (2006). Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nature Cell Biology, 8, 46–54.
Ait-Slimane, T., et al. (2009). Basolateral internalization of GPI-anchored proteins occurs via a clathrin-independent flotillin-dependent pathway in polarized hepatic cells. Molecular Biology of the Cell, 20, 3792–3800.
Cremona, M. L., Matthies, H. J., Pau, K., Bowton, E., Speed, N., Lute, B. J., Anderson, M., Sen, N., Robertson, S. D., Vaughan, R. A., Rothman, J. E., Galli, A., Javitch, J. A., & Yamamoto, A. (2011). Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT. Nature Neuroscience, 14, 469–477.
Fecchi, K., Volonte, D., Hezel, M. P., Schmeck, K., & Galbiati, F. (2006). Spatial and temporal regulation of GLUT4 translocation by flotillin-1 and caveolin-3 in skeletal muscle cells. The FASEB Journal, 20, 705–707.
Ge, L., et al. (2011). Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake. Proceedings of the National Academy of Sciences, 108, 551–556.
Park, M.-Y., et al. (2016). Role of flotillins in the endocytosis of GPCR in salivary gland epithelial cells. Biochemical and Biophysical Research Communications, 476, 237–244.
Schneider, A., Rajendran, L., Honsho, M., Gralle, M., Donnert, G., Wouters, F., Hell, S. W., & Simons, M. (2008). Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. The Journal of Neuroscience, 28, 2874–2882.
Yamamoto, H., Umeda, D., Matsumoto, S., & Kikuchi, A. (2017). LDL switches the LRP6 internalization route from flotillin dependent to clathrin dependent in hepatic cells. Journal of Cell Science, 130, 3542–3556.
Carcea, I., Ma'ayan, A., Mesias, R., Sepulveda, B., Salton, S. R., & Benson, D. L. (2010). Flotillin-mediated endocytic events dictate cell type-specific responses to Semaphorin 3A. The Journal of Neuroscience, 30, 15317–15329.
Lee, T.-H., McKleroy, W., Khalifeh-Soltani, A., Sakuma, S., Lazarev, S., Riento, K., Nishimura, S. L., Nichols, B. J., & Atabai, K. (2014). Functional genomic screen identifies novel mediators of collagen uptake. Molecular Biology of the Cell, 25, 583–593.
Walton, J. R., Frey, H. A., Vandre, D. D., Kwiek, J. J., Ishikawa, T., Takizawa, T., Robinson, J. M., & Ackerman 4th, W. E. (2013). Expression of flotillins in the human placenta: potential implications for placental transcytosis. Histochemistry and Cell Biology, 139, 487–500.
Martins, L., Leme, A. F., Kantovitz, K. R., de Luciane Martins, E. N., Sallum, E. A., Casati, M. Z., & Nociti Jr., F. H. (2017). Leucine-rich amelogenin peptide (LRAP) uptake by cementoblast requires flotillin-1 mediated endocytosis: LRAP cell uptake requires flotillin-1. Journal of Cellular Physiology, 232, 556–565.
Ren, K., Gao, C., Zhang, J., Wang, K., Xu, Y., Wang, S. B., Wang, H., Tian, C., Shi, Q., & Dong, X. P. (2013). Flotillin-1 mediates PrPC endocytosis in the cultured cells during Cu2+ stimulation through molecular interaction. Molecular Neurobiology, 48, 631–646.
Payne, C. K., Jones, S. A., Chen, C., & Zhuang, X. (2007). Internalization and trafficking of cell surface proteoglycans and proteoglycan-binding ligands. Traffic, 8, 389–401.
Johannes, L., Parton, R. G., Bassereau, P., & Mayor, S. (2015). Building endocytic pits without clathrin. Nature Reviews. Molecular Cell Biology, 16, 311–321.
Riento, K., et al. (2018). Flotillin proteins recruit sphingosine to membranes and maintain cellular sphingosine-1-phosphate levels. PLoS One, 13, e0197401.
Shen, H., Giordano, F., Wu, Y., Chan, J., Zhu, C., Milosevic, I., Wu, X., Yao, K., Chen, B., Baumgart, T., Sieburth, D., & de Camilli, P. (2014). Coupling between endocytosis and sphingosine kinase 1 recruitment. Nature Cell Biology, 16, 652–662.
Lima, S., Milstien, S., & Spiegel, S. (2017). Sphingosine and sphingosine kinase 1 involvement in endocytic membrane trafficking. The Journal of Biological Chemistry, 292, 3074–3088.
Renard, H.-F., Simunovic, M., Lemière, J., Boucrot, E., Garcia-Castillo, M. D., Arumugam, S., Chambon, V., Lamaze, C., Wunder, C., Kenworthy, A. K., Schmidt, A. A., McMahon, H., Sykes, C., Bassereau, P., & Johannes, L. (2015). Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis. Nature, 517, 493–496.
Solis, G. P., Hülsbusch, N., Radon, Y., Katanaev, V. L., Plattner, H., & Stuermer, C. A. (2013). Reggies/flotillins interact with Rab11a and SNX4 at the tubulovesicular recycling compartment and function in transferrin receptor and E-cadherin trafficking. Molecular Biology of the Cell, 24, 2689–2702.
Leprince, C. (2003). Sorting nexin 4 and amphiphysin 2, a new partnership between endocytosis and intracellular trafficking. Journal of Cell Science, 116, 1937–1948.
Rainero, E., & Norman, J. C. (2013). Late endosomal and lysosomal trafficking during integrin-mediated cell migration and invasion: cell matrix receptors are trafficked through the late endosomal pathway in a way that dictates how cells migrate. BioEssays, 35, 523–532.
Cornfine, S., Himmel, M., Kopp, P., el Azzouzi, K., Wiesner, C., Krüger, M., Rudel, T., & Linder, S. (2011). The kinesin KIF9 and reggie/flotillin proteins regulate matrix degradation by macrophage podosomes. Molecular Biology of the Cell, 22, 202–215.
Marchesin, V., Castro-Castro, A., Lodillinsky, C., Castagnino, A., Cyrta, J., Bonsang-Kitzis, H., Fuhrmann, L., Irondelle, M., Infante, E., Montagnac, G., Reyal, F., Vincent-Salomon, A., & Chavrier, P. (2015). ARF6–JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. The Journal of Cell Biology, 211, 339–358.
Meister, M., et al. (2017). Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo. Oncogenesis, 6, e344.
Tu, C., et al. (2010). Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions. Proceedings of the National Academy of Sciences, 107, 16107–16112.
Guo, A. Y., et al. (2017). Flotilin-1 promotes the tumorigenicity and progression of malignant phenotype in human lung adenocarcinoma. Cancer Biology & Therapy, 18, 715–722.
Lin, C., Wu, Z., Lin, X., Yu, C., Shi, T., Zeng, Y., Wang, X., Li, J., & Song, L. (2011). Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a. Clinical Cancer Research, 17, 3089–3099.
Kurrle, N., et al. (2013). Phosphatidylinositol 3-kinase dependent upregulation of the epidermal growth factor receptor upon flotillin-1 depletion in breast cancer cells. BMC Cancer, 13, 575.
Ye, D. M., Ye, S. C., Yu, S. Q., Shu, F. F., Xu, S. S., Chen, Q. Q., Wang, Y. L., Tang, Z. T., & Pan, C. (2019). Drug-resistance reversal in colorectal cancer cells by destruction of flotillins, the key lipid rafts proteins. Neoplasma, 66, 576–583.
Solis, G. P., Schrock, Y., Hülsbusch, N., Wiechers, M., Plattner, H., & Stuermer, C. A. (2012). Reggies/flotillins regulate E-cadherin-mediated cell contact formation by affecting EGFR trafficking. Molecular Biology of the Cell, 23, 1812–1825.
Amaddii, M., Meister, M., Banning, A., Tomasovic, A., Mooz, J., Rajalingam, K., & Tikkanen, R. (2012). Flotillin-1/Reggie-2 protein plays dual role in activation of receptor-tyrosine kinase/mitogen-activated protein kinase signaling. The Journal of Biological Chemistry, 287, 7265–7278.
Villaseñor, R., Kalaidzidis, Y., & Zerial, M. (2016). Signal processing by the endosomal system. Current Opinion in Cell Biology, 39, 53–60.
Rivera-Milla, E., Stuermer, C. A., & Málaga-Trillo, E. (2006). Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain. Cellular and Molecular Life Sciences, 63, 343–357.
Roitbak, T., Surviladze, Z., Tikkanen, R., & Wandinger-Ness, A. (2005). A polycystin multiprotein complex constitutes a cholesterol-containing signalling microdomain in human kidney epithelia. The Biochemical Journal, 392, 29–38.
Acknowledgments
We thank our colleagues Mallory Genest and Himanshu Malhotra for stimulating discussions.
Funding
This work was financially supported by the Fondation pour la Recherche Médicale (FRM). C.G.R. was financially supported by the Institut national de la Santé et de la Recherche Médicale.
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Gauthier-Rouvière, C., Bodin, S., Comunale, F. et al. Flotillin membrane domains in cancer. Cancer Metastasis Rev 39, 361–374 (2020). https://doi.org/10.1007/s10555-020-09873-y
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DOI: https://doi.org/10.1007/s10555-020-09873-y