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J Cell Biol. 2017 Jul 3;216(7):2107-2130. doi: 10.1083/jcb.201506024. Epub 2017 May 26.

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

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Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
Department of Surgical Sciences, C.I.R. Dental School, University of Torino, Torino, Italy.
Laboratoire de Physiologie cellulaire, Institut National de la Santé et de la Recherche Médicale U1003, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université de Lille, Villeneuve d'Ascq, France.
Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.
BICeL Campus Lille1, FR3688 FRABio, Université de Lille, Villeneuve d'Ascq, France.
Department of Mathematical Sciences, Politecnico di Torino, Torino, Italy.
Nanostructured Interfaces and Surfaces Centre of Excellence, University of Torino, Torino, Italy.
Cancer Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY.
Centre National de la Recherche Scientifique, Institut Pasteur de Lille, UMR 8161 - Mechanisms of Tumorigenesis and Target Therapies, Universite de Lille, Lille, France.
Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy


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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