A Kinase-Independent Role for EGF Receptor in Autophagy Initiation
Open accessAbstract
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.
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Erlotinib blocked p-EGFR in POS-fed RPE-J cells at 3 h and 6 h.
“Incubation of RPE-J cells with erlotinib, a specific EGFR tyrosine kinase inhibitor 38,39 blocked p-EGFR in POS-fed RPE-J cells at 3 h and 6 h (Fig. 6B, bottom images).”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [39]
Erlotinib is a specific EGFR tyrosine kinase inhibitor.
“Incubation of RPE-J cells with erlotinib, a specific EGFR tyrosine kinase inhibitor 38,39”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [39]
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References 58 · Cited by 223
- Authors
- Tan, X., Thapa, N., Sun, Y., & Anderson, R. A.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Anderson, Richard A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 145-160
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4297316
- OpenAlex
- W2052858451
- Cited by
- 223
- References
- 58
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 7 · 2023: 18 · 2022: 16 · 2021: 18 · 2020: 31 · 2019: 30 · 2018: 20 · 2017: 20 · 2016: 24 · 2015: 19
- FWCI
- 21.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL051952)
- National Cancer Institute (R01CA104708, CA104708)
- National Institute of General Medical Sciences (R01GM057549, GM 057549)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- epidermal growth factor receptor, autophagy initiation, LAPTM4B, Rubicon, Beclin-1, serum deprivation, cancer metabolism, kinase-independent signaling, tumor cell survival
- MeSH terms
- Erlotinib Hydrochloride, Autophagy-Related Proteins, Beclin-1, Gefitinib, Autophagy, Humans, Membrane Proteins, Quinazolines, Endosomes, Oncogene Proteins, Vesicular Transport Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, HEK293 Cells, ErbB Receptors
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