Direct interaction of Rnd1 with FRS2β regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells
Direct interaction of Rnd1 with FRS2β regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells
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DOI：
10.1074/jbc.m411356200
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发表时间：
2005-05-06
影响因子：
4.8
通讯作者：
Negishi, M
中科院分区：
文献类型：
--
作者：
Harada, A;Katoh, H;Negishi, M
Rho家族的小GTP酶已经涉及肌动蛋白细胞骨架的重组和随后的各种细胞中的形态学变化。Rnd 1是该家族的一员，具有低的内在GT3活性，并对RhoA信号传导发挥拮抗作用。然而，Rnd 1的活性是如何调节的尚未阐明。在这里，我们已经证明，Rnd 1直接与FRS 2 α和FRS 2 β，这是成纤维细胞生长因子（FGF）受体的对接蛋白，并在FGF诱导的细胞内信号中发挥重要作用。FRS 2 β与Rnd 1的相互作用抑制了Rnd 1对RhoA的抑制作用。Rnd 1结合FRS 2 β的COOH末端区域，包括与Shp 2相互作用所必需的酪氨酸残基。当FGF受体1被激活时，它磷酸化FRS 2 β，募集Shp 2，并从FRS 2 β释放Rnd 1。然后释放的Rnd 1抑制RhoA活性。此外，Rnd 1-特异性短干扰RNA敲低Rnd 1抑制FGF诱导的PC 12细胞突起生长。这些结果表明，Rnd 1的活性由FGF受体通过FRS 2 β调节，并且Rnd 1在神经突生长期间的FGF信号传导中发挥重要作用。
The Rho family of small GTPases has been implicated in the reorganization of the actin cytoskeleton and subsequent morphological changes in various cells. Rnd1, a member of this family, has a low intrinsic GTPase activity and exerts antagonistic effects on RhoA signaling. However, how the activity of Rnd1 is regulated has not yet been elucidated. Here we have demonstrated that Rnd1 directly associates with FRS2 alpha and FRS2 beta, which are docking proteins of fibroblast growth factor (FGF) receptors and play important roles in the intracellular signals induced by FGFs. The interaction of FRS2 beta with Rnd1 suppresses the inhibitory effect of Rnd1 on RhoA. Rnd1 binds to the COOH-terminal region of FRS2 beta including tyrosine residues essential for the interaction with Shp2. When FGF receptor 1 is activated, it phosphorylates FRS2 beta, recruits Shp2, and releases Rnd1 from FRS2 beta. The liberated Rnd1 then inhibits RhoA activity. Furthermore, knockdown of Rnd1 by Rnd1-specific short interfering RNAs suppress the FGF-induced neurite outgrowth in PC12 cells. These results suggest that the activity of Rnd1 is regulated by FGF receptor through FRS2 beta and that Rnd1 plays an important role in the FGF signaling during neurite outgrowth.