title: A kinase-independent role for EGF receptor in autophagy initiation.
abstract: The epidermal growth factor receptor (EGFR) is upregulated in numerous human cancers. Inhibition of EGFR signaling induces autophagy in tumor cells. Here, we report an unanticipated role for the inactive EGFR in autophagy initiation. Inactive EGFR interacts with the oncoprotein LAPTM4B that is required for the endosomal accumulation of EGFR upon serum starvation. Inactive EGFR and LAPTM4B stabilize each other at endosomes and recruit the exocyst subcomplex containing Sec5. We show that inactive EGFR, LAPTM4B, and the Sec5 subcomplex are required for basal and starvation-induced autophagy. LAPTM4B and Sec5 promote EGFR association with the autophagy inhibitor Rubicon, which in turn disassociates Beclin 1 from Rubicon to initiate autophagy. Thus, the oncoprotein LAPTM4B facilitates the role of inactive EGFR in autophagy initiation. This pathway is positioned to control tumor metabolism and promote tumor cell survival upon serum deprivation or metabolic stress.
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tan
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Thapa
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706, USA. Electronic address: raanders@wisc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C470182:EXOC2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C477083:LAPTM4B protein, human; D008565:Membrane Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C552537:RUBCN protein, human; D033921:Vesicular Transport Proteins; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib