PMID- 15271882 OWN - NLM STAT- MEDLINE DCOM- 20041130 LR - 20211203 IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 145 IP - 11 DP - 2004 Nov TI - 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. PG - 4976-84 AB - 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. FAU - Kuribayashi, Ami AU - Kuribayashi A AD - 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. FAU - Kataoka, Keiko AU - Kataoka K FAU - Kurabayashi, Tohru AU - Kurabayashi T FAU - Miura, Masahiko AU - Miura M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20040722 PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Enzyme Inhibitors) RN - 0 (GRB2 Adaptor Protein) RN - 0 (GRB2 protein, human) RN - 0 (HBEGF protein, human) RN - 0 (Heparin-binding EGF-like Growth Factor) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Quinazolines) RN - 0 (SHC1 protein, human) RN - 0 (Shc Signaling Adaptor Proteins) RN - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1) RN - 0 (Tyrphostins) RN - 170449-18-0 (RTKI cpd) RN - 62229-50-9 (Epidermal Growth Factor) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Adaptor Proteins, Signal Transducing/metabolism MH - Cell Line, Tumor MH - Enzyme Inhibitors/pharmacology MH - Epidermal Growth Factor/metabolism/pharmacology MH - ErbB Receptors/*metabolism MH - GRB2 Adaptor Protein MH - Heparin-binding EGF-like Growth Factor MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology MH - Intercellular Signaling Peptides and Proteins MH - Mitogen-Activated Protein Kinases/metabolism MH - *Mouth Neoplasms MH - Phosphorylation/drug effects MH - Protein Serine-Threonine Kinases/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Proto-Oncogene Proteins c-akt MH - Proto-Oncogene Proteins c-raf/metabolism MH - Quinazolines MH - Receptor Cross-Talk/physiology MH - Receptor, IGF Type 1/metabolism MH - Shc Signaling Adaptor Proteins MH - Signal Transduction/drug effects/*physiology MH - Src Homology 2 Domain-Containing, Transforming Protein 1 MH - Tyrphostins/antagonists & inhibitors/pharmacology MH - ras Proteins/metabolism EDAT- 2004/07/24 05:00 MHDA- 2004/12/16 09:00 CRDT- 2004/07/24 05:00 PHST- 2004/07/24 05:00 [pubmed] PHST- 2004/12/16 09:00 [medline] PHST- 2004/07/24 05:00 [entrez] AID - en.2004-0713 [pii] AID - 10.1210/en.2004-0713 [doi] PST - ppublish SO - Endocrinology. 2004 Nov;145(11):4976-84. doi: 10.1210/en.2004-0713. Epub 2004 Jul 22.