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

EMBO J. 2006 Sep 20;25(18):4195-206. doi: 10.1038/sj.emboj.7601297. Epub 2006 Aug 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cisplatin / pharmacology
  • Clathrin / metabolism
  • Endocytosis / radiation effects
  • Enzyme Activation
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • HeLa Cells
  • Humans
  • Kinetics
  • Models, Biological
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin / metabolism
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Clathrin
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • ErbB Receptors
  • p38 Mitogen-Activated Protein Kinases
  • rab5 GTP-Binding Proteins
  • Cisplatin