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Updated: Sep 20, 2025

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The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy

Yuan Huang1, Shi Li1, Qinfeng Liu1

  • 1National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.

Cell Death & Disease
|June 6, 2022
PubMed

Insights

Lymphocyte-specific protein tyrosine kinase (LCK) interacts with the TRPM8 channel, enhancing its function and promoting pancreatic cancer cell growth. This LCK-TRPM8 axis highlights new therapeutic targets for pancreatic cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Transient receptor potential melastatin 8 (TRPM8) is a Ca2+-permeable channel implicated in diseases, including pancreatic cancer.
  • The precise mechanisms underlying TRPM8 dysfunction in disease remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular interactions and regulatory mechanisms of TRPM8.
  • To investigate the role of TRPM8 in pancreatic cancer progression.

Main Methods:

  • Co-immunoprecipitation assays to identify protein interactions.
  • Electrophysiology to measure TRPM8 channel activity.
  • Western blotting to assess protein phosphorylation and ubiquitination.
  • Cell proliferation, migration, and tumorigenesis assays in pancreatic cancer models.

Main Results:

  • Lymphocyte-specific protein tyrosine kinase (LCK) directly interacts with TRPM8 and enhances its channel activity by promoting phosphorylation at Y1022 and multimerization.
  • The 14-3-3ζ protein binds to TRPM8, modulating its multimerization, with LCK enhancing this interaction.
  • TRPM8 phosphorylation at Y1022 feedback regulates LCK activity.
  • TRPM8 phosphorylation at Y1022 is crucial for pancreatic cancer cell proliferation, migration, and tumorigenesis.

Conclusions:

  • The LCK-14-3-3ζ-TRPM8 signaling axis regulates TRPM8 assembly, channel function, and LCK activity.
  • This axis represents a potential therapeutic target for pancreatic cancer.

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