Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway
Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway
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DOI：
10.1038/ncb867
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发表时间：
2002-11-01
影响因子：
21.3
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Hanafusa, H;Torii, S;Nishida, E
Sprouty (Spry) 抑制受体酪氨酸激酶的信号传导；然而，该功能的分子机制尚未明确。在这里，我们表明，在受到生长因子刺激后，Spry1 和 Spry2 易位到质膜并在保守的酪氨酸上磷酸化。接下来，它们与衔接蛋白 Grb2 结合，并抑制 Grb2-Sos 复合物向成纤维细胞生长因子受体 (FGFR) 对接衔接蛋白 FRS2 或 Shp2 的募集。 Spry 的膜易位是其磷酸化所必需的，而磷酸化对其抑制剂活性至关重要。源自小鼠 Spry2 的酪氨酸磷酸化八肽可在体外抑制 Grb2 结合 FRS2、Shp2 或小鼠 Spry2，并阻断生长因子刺激的细胞中细胞外信号调节激酶 (ERK) 的激活。非磷酸化的 Spry 突变体不能结合 Grb2，并充当显性失活，诱导 ERK 响应 FGF 的延长激活，并促进 FGF 诱导的 PC12 细胞中神经突的生长。我们的研究结果表明，Spry 在负反馈机制中发挥作用，其中其抑制剂活性通过翻译后机制快速且可逆地控制。
Sprouty (Spry) inhibits signalling by receptor tyrosine kinases; however, the molecular mechanism underlying this function has not been defined. Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine. Next, they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos complex either to the fibroblast growth factor receptor (FGFR) docking adaptor protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its phosphorylation, which is essential for its inhibitor activity. A tyrosine-phosphorylated octapeptide derived from mouse Spry2 inhibits Grb2 from binding FRS2, Shp2 or mouse Spry2 in vitro and blocks activation of the extracellular-signal-regulated kinase (ERK) in cells stimulated by growth factor. A non-phosphorylated Spry mutant cannot bind Grb2 and acts as a dominant negative, inducing prolonged activation of ERK in response to FGF and promoting the FGF-induced outgrowth of neurites in PC12 cells. Our findings suggest that Spry functions in a negative feedback mechanism in which its inhibitor activity is controlled rapidly and reversibly by post-translational mechanisms.