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Article Dans Une Revue Journal of Cell Biology Année : 2017

TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1

Chiara Camillo
Donatella Valdembri
Mark Philips

Résumé

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.

Dates et versions

hal-04038990 , version 1 (21-03-2023)

Identifiants

Citer

Tullio Genova, Guillaume Grolez, Chiara Camillo, Michela Bernardini, Alexandre Bokhobza, et al.. TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1. Journal of Cell Biology, 2017, 216 (7), pp.2107-2130. ⟨10.1083/jcb.201506024⟩. ⟨hal-04038990⟩
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