p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy
Open Access
- 24 August 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 25 (18), 4195-4206
- https://doi.org/10.1038/sj.emboj.7601297
Abstract
The epidermal growth factor receptor (EGFR) frequently associates with cancer and already serves as a target for therapy. We report that inflammatory cytokines and ultraviolet (UV) irradiation respectively induce transient or sustained phosphorylation of EGFR. Subsequently, EGFR internalizes via a Clathrin‐mediated process. In cytokine‐stimulated cells, EGFR recycles back to the cell surface, whereas in irradiated cells it arrests in Rab5‐containing endosomes. Under both conditions, receptor internalization is instigated by the p38 stress‐induced kinase. The underlying mechanism entails phosphorylation of EGFR at a short segment (amino acids 1002–1022) containing multiple serines and threonines, as well as phosphorylation of two Rab5 effectors, EEA1 and GDI. Like UV irradiation, a chemotherapeutic agent activates p38 and accelerates receptor internalization. We demonstrate that abrogating EGFR internalization reduces the efficacy of chemotherapy‐induced cell death. Hence, by preventing EGFR‐mediated survival signaling, the internalization route we uncovered enhances the cytotoxic effect of drugs like cis‐platinum, which may underlie interactions between chemotherapy and EGFR‐targeting drugs.This publication has 30 references indexed in Scilit:
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