PMID:25666625

Citation	Dong, A, Wodziak, D and Lowe, AW (2015) Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface. J. Biol. Chem. 290:8016-27
Abstract	The epidermal growth factor receptor (EGFR) is a well characterized receptor-tyrosine kinase that functions in development and serves a vital role in many human cancers. Understanding EGFR regulatory mechanisms, and hence approaches for clinical intervention, has focused on ligand-receptor interactions and tyrosine kinase activity. Here, we show using the NCI-H460 lung and A431 epidermoid human cancer cell lines that EGFR binding to anterior gradient homolog 2 (AGR2) in the endoplasmic reticulum is required for receptor delivery to the plasma membrane and thus EGFR signaling. Reduced AGR2 protein levels or mutation of an essential cysteine in the active site result in decreased cell surface EGFR and a concomitant decrease in signaling as reflected by AREG, EGR1, and FOS expression. Similar to previously described EGFR nulls, an AGR2 null also resulted in embryonic lethality. Consistent with its role in regulating EGFR-mediated signaling, AGR2 expression is also enhanced in many human cancers and promotes the transformed phenotype. Furthermore, EGFR-mediated signaling in NCI-H460 cells, which are resistant to the tyrosine kinase inhibitor AG1478, is also disrupted with reduced AGR2 expression. The results provide insights into why cancer prognosis or response to therapy often does not correlate with EGFR protein or RNA levels because they do not reflect delivery to the cell surface where signaling is initiated. AGR2, therefore, represents a novel post-translational regulator of EGFR-mediated signaling and a promising target for treating human cancers.
Links	PubMed PMC4375459 Online version:10.1074/jbc.M114.623207
Keywords	Animals; CHO Cells; Cell Line, Tumor; Cell Membrane/metabolism; Cricetinae; Cricetulus; Cystine/metabolism; Endoplasmic Reticulum/metabolism; Humans; Mice, Inbred C57BL; Mice, Transgenic; Protein Kinase Inhibitors/pharmacology; Protein Transport; Proteins/metabolism; Quinazolines/pharmacology; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction; Thioredoxins/metabolism; Tyrphostins/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:AGR2	involved_in	GO:0048639: positive regulation of developmental growth	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:AGR2	involved_in	GO:0048546: digestive tract morphogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AGR2	enables	GO:0005154: epidermal growth factor receptor binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P00533	F		Seeded From UniProt	complete
HUMAN:AGR2	NOT|involved_in	GO:0034976: response to endoplasmic reticulum stress	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AGR2	involved_in	GO:1903078: positive regulation of protein localization to plasma membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P00533)	Seeded From UniProt	complete
HUMAN:AGR2	involved_in	GO:0045742: positive regulation of epidermal growth factor receptor signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P00533)	Seeded From UniProt	complete
HUMAN:EGFR	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O95994	F		Seeded From UniProt	complete
HUMAN:EGFR	part_of	GO:0009986: cell surface	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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