title: EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.
abstract: Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic processes, including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated VPS34 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors and restores autophagy in non-small-cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance.
authors.affiliation: Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.forename: Nils
authors.initials: N
authors.lastname: Becker
authors.forename: Matthew
authors.initials: M
authors.lastname: Anderson
authors.forename: Rhea
authors.initials: R
authors.lastname: Sumpter
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Lisa
authors.initials: L
authors.lastname: Kinch
authors.forename: Prasad
authors.initials: P
authors.lastname: Koduru
authors.forename: Christhunesa S
authors.initials: CS
authors.lastname: Christudass
authors.forename: Robert W
authors.initials: RW
authors.lastname: Veltri
authors.forename: Nick V
authors.initials: NV
authors.lastname: Grishin
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010766:Phosphorylation
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
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