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Updated: Sep 23, 2025

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TRPM8-Rap1A Interaction Sites as Critical Determinants for Adhesion and Migration of Prostate and Other Epithelial

Giorgia Chinigò1,2, Guillaume P Grolez2, Madelaine Audero1,2

  • 1Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy.

Cancers
|May 14, 2022
PubMed

Insights

The TRPM8 channel inhibits prostate cancer cell migration by interacting with and inactivating Rap1A. This protein-protein interaction offers a new therapeutic target for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The Transient Receptor Potential Melastatin 8 (TRPM8) channel is implicated in prostate cancer (PCa) progression.
  • TRPM8's role in PCa cell motility is an area of active investigation.

Purpose of the Study:

  • To elucidate the novel mechanism of PCa cell motility control by TRPM8 through direct protein-protein interaction (PPI) with the small GTPase Rap1A.
  • To identify critical residues mediating the TRPM8-Rap1A interaction and their functional consequences on cancer cell behavior.

Main Methods:

  • Active Rap1 pull-down assays and live-cell imaging were employed to assess functional interaction.
  • Molecular modeling identified putative interaction sites, which were further validated using point mutations.
  • GST-pull-down, co-immunoprecipitation, and proximity ligation assay (PLA) experiments confirmed PPI and its functional impact.

Main Results:

  • A direct PPI between TRPM8 and Rap1A was identified as a key regulator of PCa cell motility.
  • TRPM8 inhibits cell migration and adhesion by maintaining Rap1A in its inactive GDP-bound state, preventing plasma membrane activation.
  • Specific residues (E207, Y240 in TRPM8; Y32 in Rap1A) are critical for this interaction in PC3, HeLa, and MCF-7 cancer cells.

Conclusions:

  • TRPM8 exerts a protective role in cancer progression by inhibiting cell motility via Rap1A interaction.
  • This study provides a deeper understanding of TRPM8's mechanism in cancer and highlights its potential as a therapeutic target.
Keywords:
GTPaseRap1ATRPM8adhesioncalcium channelmetastasismigrationprostate cancer

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