The LCK-14-3-3ζ-TRPM8 Axis Regulates TRPM8 Function/assembly and Promotes Pancreatic Cancer Malignancy

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Jun 6

PMID 35665750

Authors

Yuan Huang

Shi Li

Qinfeng Liu

Zhijie Wang

Shunyao Li

Lei Liu

Weiwei Zhao

Kai Wang

Rui Zhang

Longfei Wang

Ming Wang

Declan William Ali

Marek Michalak

Xing-Zhen Chen

Cefan Zhou

Jingfeng Tang

Affiliations

Soon will be listed here.

Abstract

Transient receptor potential melastatin 8 (TRPM8) functions as a Ca-permeable channel in the plasma membrane (PM). Dysfunction of TRPM8 is associated with human pancreatic cancer and several other diseases in clinical patients, but the underlying mechanisms are unclear. Here, we found that lymphocyte-specific protein tyrosine kinase (LCK) directly interacts with TRPM8 and potentiates TRPM8 phosphorylation at Y1022. LCK positively regulated channel function characterized by increased TRPM8 current densities by enhancing TRPM8 multimerization. Furthermore, 14-3-3ζ interacted with TRPM8 and positively modulated channel multimerization. LCK significantly enhanced the binding of 14-3-3ζ and TRPM8, whereas mutant TRPM8-Y1022F impaired TRPM8 multimerization and the binding of TRPM8 and 14-3-3ζ. Knockdown of 14-3-3ζ impaired the regulation of TRPM8 multimerization by LCK. In addition, TRPM8 phosphotyrosine at Y1022 feedback regulated LCK activity by inhibiting Tyr505 phosphorylation and modulating LCK ubiquitination. Finally, we revealed the importance of TRPM8 phosphorylation at Y1022 in the proliferation, migration, and tumorigenesis of pancreatic cancer cells. Our findings demonstrate that the LCK-14-3-3ζ-TRPM8 axis for regulates TRPM8 assembly, channel function, and LCK activity and maybe provide potential therapeutic targets for pancreatic cancer.

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