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

Tullio Genova1,2, Guillaume P Grolez3, Chiara Camillo4

  • 1Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.

The Journal of Cell Biology
|May 28, 2017
PubMed

Insights

The TRPM8 channel inhibits endothelial cell migration through a novel non-channel function, acting as a Rap1 GTPase inhibitor. This discovery reveals a new mechanism controlling vascular cell behavior and angiogenesis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Endothelial cell adhesion and migration are crucial for angiogenesis, a process often dysregulated in tumor growth and metastasis.
  • The TRPM8 channel was previously suggested to inhibit prostate cancer cell motility, but its role in vascular endothelial cells remained unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which TRPM8 influences vascular endothelial cell behavior.
  • To investigate a potential non-channel function of TRPM8 in regulating endothelial cell motility.

Main Methods:

  • Investigated TRPM8's interaction with Rap1 GTPase.
  • Assessed the impact of TRPM8 on Rap1 intracellular trafficking.
  • Examined the effects on integrin activation, endothelial cell adhesion, migration, and in vitro angiogenesis models.

Main Results:

  • TRPM8 functions independently of its channel pore activity to inhibit endothelial cell motility.
  • TRPM8 directly interacts with Rap1 GTPase, retaining it intracellularly and preventing its trafficking to the plasma membrane.
  • This inhibition of Rap1 GTPase impairs integrin activation, leading to reduced endothelial cell adhesion, migration, tube formation, and spheroid sprouting.

Conclusions:

  • TRPM8 possesses a novel, pore-independent function as a Rap1 GTPase inhibitor.
  • This mechanism significantly impacts vascular endothelial cell behavior, particularly migration.
  • Endogenous TRPM8 plays a critical role in regulating angiogenesis by inhibiting endothelial cell motility.

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