The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy.
The LCK-14-3-3ζ-TRPM8 axis regulates TRPM8 function/assembly and promotes pancreatic cancer malignancy.
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DOI：
10.1038/s41419-022-04977-5
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发表时间：
2022-06-04
影响因子：
9
通讯作者：
Tang, Jingfeng
中科院分区：
文献类型：
--
作者：
Huang, Yuan;Li, Shi;Liu, Qinfeng;Wang, Zhijie;Li, Shunyao;Liu, Lei;Zhao, Weiwei;Wang, Kai;Zhang, Rui;Wang, Longfei;Wang, Ming;Ali, Declan William;Michalak, Marek;Chen, Xing-Zhen;Zhou, Cefan;Tang, Jingfeng
瞬时受体电位Melastatin 8(TRPM8)在质膜(PM)上起着钙离子通道的作用。在临床患者中，TRPM8功能障碍与人胰腺癌和其他几种疾病有关，但其潜在机制尚不清楚。在这里，我们发现淋巴细胞特异性蛋白酪氨酸激酶(LCK)直接与TRPM8相互作用，并在Y1022增强TRPM8的磷酸化。LCK正向调节通道功能，其特征是通过增强TRPM8多聚体而增加TRPM8的电流密度。此外，14-3-3ζ与TRPM8相互作用，并正向调制通道多聚体。LCK显著增强了14-3-3ζ与TRPM8的结合，而突变体TRPM8-Y1022F抑制了TRPM8的多聚化及TRPM8与14-3-3ζ的结合。敲除14-3-3TRPM8基因后，ζ对TRPM8多聚体的调节作用减弱。此外，位于Y1022的TRPM8磷酸酪氨酸通过抑制Tyr505磷酸化和调节LCK泛素化来调节LCK活性。最后，我们揭示了Y1022位TRPM8磷酸化在胰腺癌细胞增殖、迁移和肿瘤发生中的重要作用。我们的研究结果表明，LCK-14-3-3ζ-TRPM8轴调节TRPM8的组装、通道功能和LCK活性，可能为胰腺癌提供潜在的治疗靶点。
Transient receptor potential melastatin 8 (TRPM8) functions as a Ca2+-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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影响因子：
7.4
作者：
Liu B;Fan L;Balakrishna S;Sui A;Morris JB;Jordt SE
通讯作者：
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影响因子：
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影响因子：
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DOI：
10.1083/jcb.141.1.281
发表时间：
1998-04-06
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
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DOI：
10.2147/dddt.s80207
发表时间：
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期刊：
Drug design, development and therapy
影响因子：
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作者：
Chen R;Chen B
通讯作者：
Chen B