Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1

被引:212
作者
Sasaki, A
Taketomi, T
Kato, R
Saeki, K
Nonami, A
Sasaki, M
Kuriyama, M
Saito, N
Shibuya, M
Yoshimura, A
机构
[1] Kyushu Univ, Div Mol & Cellular Immunol, Med Inst Bioregulat, Higashi Ku, Fukuoka 8128582, Japan
[2] Kobe Univ, Mol Pharmacol Lab, Biosignal Res Ctr, Nada Ku, Kobe, Hyogo 6578501, Japan
[3] Univ Tokyo, Div Genet, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
关键词
D O I
10.1038/ncb978
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:427 / 432
页数:6
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