EGFR Signaling Requires a Specific Endoplasmic Reticulum Thioredoxin for the Post-Translational Control of Receptor Presentation to the Cell Surface [Molecular Bases of Disease]

February 9th, 2015 by Dong, A., Wodziak, D., Lowe, A. W.

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, have 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.
  • Posted in Journal of Biological Chemistry, Publications
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