Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1
Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1
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DOI：
10.1038/ncb978
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发表时间：
2003-05-01
影响因子：
21.3
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
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作者：
Sasaki, A;Taketomi, T;Yoshimura, A
包括Raf、促分裂原活化蛋白激酶（MAPK）激酶和细胞外信号调节激酶（ERK）的信号级联在细胞调节的许多方面都很重要（1-3）。Raf通过Ras依赖性和Ras非依赖性机制激活（4-6），但Raf激活的调节机制仍不清楚（7-9）。两个膜结合分子家族，Sprouty和Sprouty相关的含EVH 1结构域蛋白（Spred）已被鉴定（10-13），并被表征为生长因子诱导的ERK激活的负调节因子（14-25）。但哺乳动物Sproutys的分子功能还不清楚。在这里，我们表明，哺乳动物Sprouty 4抑制血管上皮生长因子（VEGF）诱导的，Ras独立的激活Raf 1，但不影响表皮生长因子（EGF）诱导的，Ras依赖的激活Raf 1。Sprouty 4通过其羧基末端富含半胱氨酸的结构域与Raf 1结合，并且这种结合对于Sprouty 4的抑制活性是必需的。此外，含有保守酪氨酸残基的氨基末端区域的Sprouty 4突变体仍然抑制VEGF诱导的ERK途径，所述保守酪氨酸残基是抑制成纤维细胞生长因子信号传导所必需的（19，25）。我们的研究结果表明，受体酪氨酸激酶使用不同的途径Raf和ERK激活和Sprouty 4差异调节这些途径。
The signalling cascade including Raf, mitogen-activated protein kinase (MAPK) kinase and extracellular-signal-regulated kinase (ERK) is important in many facets of cellular regulation(1-3). Raf is activated through both Ras-dependent and Ras-independent mechanisms(4-6), but the regulatory mechanisms of Raf activation remain unclear(7-9). Two families of membrane-bound molecules, Sprouty and Sprouty-related EVH1-domain-containing protein (Spred) have been identified(10-13) and characterized as negative regulators of growth-factor-induced ERK activation(14-25). But the molecular functions of mammalian Sproutys have not been clarified. Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. In addition, Sprouty4 mutants of the amino-terminal region containing the conserved tyrosine residue, which is necessary for suppressing fibroblast growth factor signalling(19,25), still inhibit the VEGF-induced ERK pathway. Our results show that receptor tyrosine kinases use distinct pathways for Raf and ERK activation and that Sprouty4 differentially regulates these pathways.