biostudies-literatureUnknown1(4)Zhou CEpidermal 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 <i>in vitro</i> and <i>in vivo.</i> Moreover, EGFR-TKIs induCell insight100045https://www.ebi.ac.uk/biostudies/studies/S-EPMC10120315biostudies-literaturePhosphorylated STYK1 restrains the inhibitory role of EGFR in autophagy initiation and EGFR-TKIs sensitivity.PMC10120315Dong XLiang YMichalak MZhang RXiao SChen XZWang MQian XTang JHuang YZhou CLyu HHu MLiang KAli DWTang YfalsePhosphorylated STYK1 restrains the inhibitory role of EGFR in autophagy initiation and EGFR-TKIs sensitivity.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 <i>in vitro</i> and <i>in vivo.</i> Moreover, EGFR-TKIs indu2022-01-01T00:00:00Z2022 Aug2025-04-22T00:31:56.055Z2025-04-05T19:37:00.737ZS-EPMC101203153719285910.1016/j.cellin.2022.100045