TY - JOUR
T1 - XEGFR-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance
AU - Wei, Yongjie
AU - Zou, Zhongju
AU - Becker, Nils
AU - Anderson, Matthew
AU - Sumpter, Rhea
AU - Xiao, Guanghua
AU - Kinch, Lisa
AU - Koduru, Prasad
AU - Christudass, Christhunesa S.
AU - Veltri, Robert W.
AU - Grishin, Nick V.
AU - Peyton, Michael
AU - Minna, John
AU - Bhagat, Govind
AU - Levine, Beth
N1 - Funding Information:
We thank Noboru Mizushima, Tamotsu Yoshimori, and Sandra Schmid for supplying critical reagents, Haley Harrington for assistance with manuscript preparation, and Lori Nguyen for technical assistance. This work was supported by National Institutes of Health grants NCI RO1 84254 and NCI RO1 109618 to B.L. and the Lung Cancer SPORE P50CA70907 to J.M.
PY - 2013/9/12
Y1 - 2013/9/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.08.015
DO - 10.1016/j.cell.2013.08.015
M3 - Article
C2 - 24034250
AN - SCOPUS:84884262668
SN - 0092-8674
VL - 154
SP - 1269
JO - Cell
JF - Cell
IS - 6
ER -