Journal
JOURNAL OF CELL BIOLOGY
Volume 216, Issue 7, Pages 2107-2130Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201506024
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Funding
- Ministere de l'Education Nationale
- Institut National de la Sante et de la Recherche Medicale
- Institut National du Cancer [INCa-PLB IO14-213]
- Fondation ARC pour la recherche sur le cancer [PJA 20141202010]
- Association pour la Recherche sur les Tumeurs de la Prostate
- University of Torino
- Compagnia di San Paolo [Torino_call2014_L2_130]
- Associazione Italiana per la Ricerca sul Cancro [9211, 16702]
- Associazione Augusto per la Vita
- Fondazione Piemontese per la Ricerca sul Cancro (grant ONLUS) [MIUR 2010 VASCHETTO - 5 per mille 2010 MIUR]
- Universite Franco Italienne Vinci program
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Endothelial 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.
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