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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

Molecular Diagnosis and Therapeutics (A.K., K.K., M.M.) and Oral and Maxillofacial Radiology (A.K., T.K.), Department of Oral Restitution, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Address all correspondence and requests for reprints to: Dr. Masahiko Miura, Molecular Diagnosis and Therapeutics, Department of Oral Restitution, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. E-mail: masa.mdth{at}tmd.ac.jp.

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.

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