XEGFR-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance

Yongjie Wei, Zhongju Zou, Nils Becker, Matthew Anderson, Rhea Sumpter, Guanghua Xiao, Lisa Kinch, Prasad Koduru, Christhunesa S. Christudass, Robert W. Veltri, Nick V. Grishin, Michael Peyton, John Minna, Govind Bhagat, Beth Levine

Research output: Contribution to journalArticle

265 Citations (Scopus)

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.

Original languageEnglish (US)
JournalCell
Volume154
Issue number6
DOIs
StatePublished - Sep 12 2013

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Phosphorylation
Autophagy
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Tumors
Tyrosine
Neoplasms
Cells
Non-Small Cell Lung Carcinoma
Growth Factor Receptors
Receptor Protein-Tyrosine Kinases
Heterografts
Machinery
Phosphotransferases
Chemical activation
Cues
Beclin-1
Mutation
Proteins
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

XEGFR-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. / Wei, Yongjie; Zou, Zhongju; Becker, Nils; Anderson, Matthew; Sumpter, Rhea; Xiao, Guanghua; Kinch, Lisa; Koduru, Prasad; Christudass, Christhunesa S.; Veltri, Robert W.; Grishin, Nick V.; Peyton, Michael; Minna, John; Bhagat, Govind; Levine, Beth.

In: Cell, Vol. 154, No. 6, 12.09.2013.

Research output: Contribution to journalArticle

Wei, Yongjie ; Zou, Zhongju ; Becker, Nils ; Anderson, Matthew ; Sumpter, Rhea ; Xiao, Guanghua ; Kinch, Lisa ; Koduru, Prasad ; Christudass, Christhunesa S. ; Veltri, Robert W. ; Grishin, Nick V. ; Peyton, Michael ; Minna, John ; Bhagat, Govind ; Levine, Beth. / XEGFR-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. In: Cell. 2013 ; Vol. 154, No. 6.
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