CRBM, University of Montpellier, CNRS, Montpellier, France.
Cancer Metastasis Rev. 2020 Jun;39(2):361-374. doi: 10.1007/s10555-020-09873-y.
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.
Flotillins 1 和 2 是两种普遍存在且高度保守的同源蛋白，它们在富含胆固醇和鞘脂的质膜细胞质面组装形成异四聚体。Flotillin 异四聚体可以组装成大的寡聚体，形成分子支架，调节质膜的聚集和几种受体的活性。此外， flotillins 在许多侵袭性癌中上调，也在肉瘤中上调，这与预后不良和转移形成有关。上调时， flotillins 促进质膜内陷，并诱导一种内吞途径，允许将货物蛋白靶向在 flotillins 积累的晚期内体隔室中。这些晚期内体不是降解性的，参与货物蛋白的再循环和分泌。这个上调的 Flotillin 诱导的运输（UFIT）途径的货物包括参与信号转导、黏附和细胞外基质重塑的分子，从而有利于获得导致转移形成的侵袭性细胞行为。因此，从质膜到晚期内体隔室的 flotillin 存在影响活性，甚至改变关键货物蛋白的运输和命运，有利于疾病的发展，例如肿瘤。这篇综述总结了 flotillins 的最新知识及其在癌症发展中的作用，重点介绍了它们在细胞膜重塑和囊泡运输调节中的功能。
