Phosphorylated STYK1 restrains the inhibitory role of EGFR in autophagy initiation and EGFR-TKIs sensitivity

Cefan Zhou; Xueying Dong; Ming Wang; Xuehong Qian; Miao Hu; Kai Liang; Yanyan Liang; Rui Zhang; Yuan Huang; Hao Lyu; Shuai Xiao; Yongfei Tang; Declan William Ali; Marek Michalak; Xing-Zhen Chen; Jingfeng Tang

doi:10.1016/j.cellin.2022.100045

Phosphorylated STYK1 restrains the inhibitory role of EGFR in autophagy initiation and EGFR-TKIs sensitivity

Cell Insight. 2022 Jun 16;1(4):100045. doi: 10.1016/j.cellin.2022.100045. eCollection 2022 Aug.

Authors

Cefan Zhou^{1

2}, Xueying Dong¹, Ming Wang³, Xuehong Qian¹, Miao Hu¹, Kai Liang¹, Yanyan Liang¹, Rui Zhang¹, Yuan Huang¹, Hao Lyu¹, Shuai Xiao¹, Yongfei Tang⁴, Declan William Ali⁵, Marek Michalak⁶, Xing-Zhen Chen², Jingfeng Tang¹

Affiliations

¹ National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, China.
² Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
³ Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
⁴ Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China.
⁵ Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
⁶ Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

Abstract

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation and tumorigenesis. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments, however, the molecular mechanisms has not been fully addressed. In this study, we identified EGFR interacts with STYK1, a positive autophagy regulator, in EGFR kinase activity dependent manner. We found that EGFR phosphorylates STYK1 at Y356 site and STYK1 inhibits activated EGFR mediated Beclin1 tyrosine phosphorylation and interaction between Bcl2 and Beclin1, thus enhances PtdIns3K-C1 complex assembly and autophagy initiation. We also demonstrated that STYK1 depletion increased the sensitivity of NSCLC cells to EGFR-TKIs in vitro and in vivo. Moreover, EGFR-TKIs induced activation of AMPK phosphorylates STYK1 at S304 site. STYK1 S304 collaborated with Y356 phosphorylation to enhance the EGFR-STYK1 interaction and reverse the inhibitory effects of EGFR to autophagy flux. Collectively, these data revealed new roles and cross-talk between STYK1 and EGFR in autophagy regulation and EGFR-TKIs sensitivity in NSCLC.

Keywords: Autophagy initiation; EGFR; NSCLC; Resistance; STYK1.