p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy


  • Yaara Zwang,

  • Yosef Yarden

    Corresponding author
    1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
    • Corresponding author. Department of Biological Regulation, The Weizmann Institute of Science, 1 Hertzl Street, Candiotty Building, Room 302, Rehovot 76100, Israel. Tel.: +972 8 934 3974; Fax: +972 8 934 2488; E-mail: yosef.yarden@weizmann.ac.il

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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.