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EnglishEndothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein-protein interaction, thus preventing its cytoplasm-plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration.
TRPM8 inhibits endothelial cell migration via a nonchannel function by trapping the small GTPase Rap1 / Genova, T; Grolez, Gp; Camillo, C; Bernardini, M; Bokhobza, A; Richard, E; Scianna, Marco; Lemonnier, L; Valdembri, D; Munaron, L; Philips, Mr; Mattot, V; Serini, G; Prevarskaya, N; Gkika, D; Pla, A.. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 216:7(2017), pp. 2107-2130. [10.1083/jcb.201506024]
| Titolo: | TRPM8 inhibits endothelial cell migration via a nonchannel function by trapping the small GTPase Rap1 | |
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| Data di pubblicazione: | 2017 | |
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| Digital Object Identifier (DOI): | http://dx.doi.org/10.1083/jcb.201506024 | |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
File in questo prodotto:
| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| JCB_201506024.pdf | 2a Post-print versione editoriale / Version of Record |  | Visibile a tuttiVisualizza/Apri |
http://hdl.handle.net/11583/2689387
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