Inclusion of ΑVβ3 integrin into extracellular vesicles in a caveolin-1 tyrosine-14- phosphorylation dependent manner and subsequent transfer to recipient melanoma cells promotes migration, invasion and metastasis.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2025-03-17 DOI:10.1186/s12964-025-02131-0

R Huilcaman, A Campos, P Contreras, L Simón, M Varas-Godoy, F Grünenwald, Baohai Shao, Jay Heinecke, L Lobos-Gonzalez, L Leyton, A F G Quest

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Abstract

Caveolin-1 (CAV1) is a membrane protein that promotes migration, invasion and metastasis of cancer cells when phosphorylated on tyrosine-14 (Y14) by a cell intrinsic mechanism involving the activation of a novel Rab5-Rac1 signaling axis. Moreover, CAV1 expressed in aggressive cancer cells is included into extracellular vesicles (EVs) and such EVs increase the metastatic potential of recipient lower grade cancer cells. However, the relevance of CAV1 Y14 phosphorylation in these extrinsic EV-stimulated events remained to be determined. Here we used B16F10 mouse melanoma cells over-expressing wild-type CAV1, phospho-mimetic CAV1(Y14E) or phospho-null CAV1(Y14F) as models to determine how the EV protein content was affected by Y14 phosphorylation and how these EVs modulated the metastatic potential of recipient B16F10 cells lacking CAV1. EVs from B16F10 cells over-expressing wild-type and CAV1(Y14/E) contain CAV1, and other proteins linked to signaling pathways associated with cell adhesion and migration. CAV1 inclusion in EVs was reduced by the Y14F mutation and global protein composition was also significantly different. Moreover, CAV1 wild-type and CAV1(Y14E) EVs promoted migration, as well as invasion of cells lacking CAV1 [B16F10(Mock) cells]. In addition, β3 integrin was transferred via CAV1(Y14E) EVs to B16F10 (Mock) cells, and treatment with such EVs promoted metastasis of recipient B16F10(Mock) cells. Finally, CAV1(Y14E) EV-enhanced migration, invasion and metastasis of recipient cells was blocked by anti-αVβ3 antibodies. In conclusion, CAV1 phosphorylated on Y14 not only intrinsically promotes migration, invasion and metastasis of cells expressing the protein (in cis), but also favors the inclusion of CAV1 into EVs, as well as the extrinsic acquisition of malignant traits in recipient cells, through integrin transfer (in trans).

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ΑVβ3整合素以依赖于caveolin-1酪氨酸-14磷酸化的方式进入细胞外囊泡，随后转移到受体黑色素瘤细胞，促进迁移、侵袭和转移。

Caveolin-1 （CAV1）是一种膜蛋白，当酪氨酸-14 （Y14）磷酸化时，通过一种新的Rab5-Rac1信号轴激活的细胞内在机制，促进癌细胞的迁移、侵袭和转移。此外，在侵袭性癌细胞中表达的CAV1被包括在细胞外囊泡（EVs）中，这种EVs增加了受体低级别癌细胞的转移潜力。然而，CAV1 Y14磷酸化在这些外源性ev刺激事件中的相关性仍有待确定。在这里，我们使用过表达野生型CAV1、模拟磷酸化CAV1（Y14E）或无磷酸化CAV1（Y14F）的B16F10小鼠黑色素瘤细胞作为模型，以确定Y14磷酸化如何影响EV蛋白含量，以及这些EV如何调节缺乏CAV1的受体B16F10细胞的转移潜能。来自过表达野生型和CAV1（Y14/E）的B16F10细胞的ev含有CAV1，以及与细胞粘附和迁移相关的信号通路相关的其他蛋白质。Y14F突变减少了EVs中CAV1的包涵，并且整体蛋白组成也显著不同。此外，CAV1野生型和CAV1(Y14E) ev促进了迁移，以及缺乏CAV1的细胞[B16F10（Mock）细胞]的侵袭。此外，β3整合素通过CAV1(Y14E) ev转移到B16F10（Mock）细胞中，这些ev处理促进了受体B16F10（Mock）细胞的转移。最后，抗α v β3抗体阻断CAV1(Y14E) ev增强的受体细胞迁移、侵袭和转移。综上所述，Y14上的CAV1磷酸化不仅内在地促进表达该蛋白的细胞的迁移、侵袭和转移（顺式），而且通过整合素转移（反式），有利于CAV1被纳入ev，以及受体细胞中恶性性状的外在获得。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.