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
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
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DOI：
10.1210/en.2004-0713
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发表时间：
2004-11-01
期刊：
影响因子：
4.8
通讯作者：
Miura, M
中科院分区：
文献类型：
--
作者：
Kuribayashi, A;Kataoka, K;Miura, M
IGF-I受体（IGF-IR）通过其主要下游信号分子细胞外信号调节激酶（ERK）和磷脂酰肌醇3 '-激酶/Akt参与多种生物学功能。据报道，IGF-I诱导的ERK激活（而非Akt激活）由表皮生长因子受体（EGFR）酪氨酸激酶（TK）的反式激活介导。然而，EGFR-TK依赖性激活的机制在很大程度上仍然未知。我们发现，口腔癌细胞系过度表达EGFR，Ca 9 - 22，表现出IGF-I诱导的Akt和ERK的激活，但只有后者显着降低了EGFR-TK，tyrphostin AG 1478的特异性抑制剂。在这份报告中，我们提供的证据表明，在这种细胞系中存在一种新的机制，IGF-I诱导ERK激活的方式是依赖于基础水平的EGFR-TK活性，但独立的受体反式激活。此外，我们发现c-Raf激酶可能是这种机制的关键调节因子。阐明这种独特的机制，涉及EGFR和异源受体之间的串扰可能会进一步阐明EGFR-TK抑制剂在抗肿瘤治疗中的临床应用。
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.