EGFR Modulates Monounsaturated Fatty Acid Synthesis And Study Of EGFRvA Protein Stability

Epidermal growth factor receptor(EGFR),a well-known oncogenic driver,contributes to the initiation and progression of a wide range of cancer types.Aberrant lipid metabolism including highly produced monounsaturated fatty acids(MUFA)is recognized as a hallmark of cancer.However,how EGFR regulates MUFA synthesis remains elusive.Here,we show that EGFR binds to and phosphorylates stearoyl-Co A desaturase-1(SCD1),a rate-limiting enzyme responsible for MUFA synthesis,at Y55 to maintain its protein stability,thereby increasing MUFA level to facilitate cancer growth.Moreover,EGFR-stimulated cancer growth depends on SCD1 activity.Evaluation of nonsmall cell lung cancer samples reveals a positive correlation among EGFR activation,SCD1 Y55 phosphorylation and SCD1 protein expression.Furthermore,phospho-SCD1 Y55 can serve as an independent prognostic factor for poor patient survival.Taken together,our findings uncover a novel mechanism that EGFR stabilizes SCD1 through Y55 phosphorylation,thus up-regulating MUFA synthesis to promote cancer growth.Recently,we have identified a novel EGFR isoform(EGFRv A),which has higher tumor-promoting capacity than EGFR.However,the underlying mechanism is not well understood.Here,we demonstrate that EGFRv A is more stable than EGFR.Interestingly,we observe that EGFRv A binds less to E3 ubiquitin ligase c-Cbl than EGFR does,although Y1045,a direct binding site of c-Cbl,is well phosphorylated in both of them.Further study reveals that EGFRv A cannot bind to Grb2,an important binding mediator between EGFR and c-Cbl.Thus,our study finds that EGFRv A is more stable than EGFR because of its decreased binding to c-Cbl.