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.
journal_name
Celljournal_title
Cellauthors
Wei Y,Zou Z,Becker N,Anderson M,Sumpter R,Xiao G,Kinch L,Koduru P,Christudass CS,Veltri RW,Grishin NV,Peyton M,Minna J,Bhagat G,Levine Bdoi
10.1016/j.cell.2013.08.015subject
Has Abstractpub_date
2013-09-12 00:00:00pages
1269-84issue
6eissn
0092-8674issn
1097-4172pii
S0092-8674(13)01009-Xjournal_volume
154pub_type
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