p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy.
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.
Zwang
Yaara
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Yarden
Yosef
Y
D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000528:radiation effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D002966:Clathrin; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D020696:rab5 GTP-Binding Proteins; D002945:Cisplatin