Evidence that basal activity, but not transactivation, of the epidermal growth factor receptor tyrosine kinase is required for insulin-like growth factor I-induced activation of extracellular signal-regulated kinase in oral carcinoma cells

Endocrinology. 2004 Nov;145(11):4976-84. doi: 10.1210/en.2004-0713. Epub 2004 Jul 22.

Abstract

IGF-I receptor (IGF-IR) is involved in numerous biological functions via its major downstream signaling molecules, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase/Akt. The IGF-I-induced activation of ERK, but not that of Akt, is reportedly mediated by the transactivation of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). The mechanism for the EGFR-TK-dependent activation, however, still remains largely unknown. We found that an oral carcinoma cell line overexpressing EGFR, Ca9-22, exhibited IGF-I-induced activation of both Akt and ERK, but that only the latter was significantly decreased by a specific inhibitor of EGFR-TK, tyrphostin AG1478. In this report we provide evidence for the existence in this cell line of a novel mechanism by which IGF-I induces ERK activation in a manner that is dependent on the basal level of EGFR-TK activity, but is independent of receptor transactivation. In addition, we show that c-Raf kinase is likely to be a key regulator of this mechanism. The elucidation of such a unique mechanism involving cross-talk between EGFR and heterologous receptors may shed additional light on the clinical use of EGFR-TK inhibitors in antitumor therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism*
  • GRB2 Adaptor Protein
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Insulin-Like Growth Factor I / pharmacology*
  • Intercellular Signaling Peptides and Proteins
  • Mitogen-Activated Protein Kinases / metabolism
  • Mouth Neoplasms*
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf / metabolism
  • Quinazolines
  • Receptor Cross-Talk / physiology
  • Receptor, IGF Type 1 / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrphostins / antagonists & inhibitors
  • Tyrphostins / pharmacology
  • ras Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Quinazolines
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrphostins
  • RTKI cpd
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • ErbB Receptors
  • Receptor, IGF Type 1
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • ras Proteins