Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor sprouty
Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor sprouty
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DOI：
10.1074/jbc.m312498200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Hanafusa, H;Torii, S;Nishida, E
Src同源2-含磷酸酪氨酸磷酸酶（Shp2）作为受体酪氨酸激酶（RTK）信号传导的正效应者，直接靠近激活的受体。然而，其生理底物及其在RTK信号传导中的作用机制尚未明确。在这项研究中，我们证明了spprty （Spry）可能是Shp2的靶点。Spry是一种保守的RTK信号抑制剂，其酪氨酸磷酸化是其抑制活性的必要条件。Shp2在体内和体外均能使Spry上成纤维细胞生长因子受体诱导的磷酸酪氨酸去磷酸化。shp2介导的Spry去磷酸化导致Spry与Grb2分离。此外，Shp2可以逆转Spry对fgf诱导的神经突生长和MAP激酶激活的抑制作用。这些发现表明，Shp2通过使Spry去磷酸化和失活，在RTK信号传导中起着积极的调节作用。
Src homology 2-containing phosphotyrosine phosphatase (Shp2) functions as a positive effector in receptor tyrosine kinase (RTK) signaling immediately proximal to activated receptors. However, neither its physiological substrate(s) nor its mechanism of action in RTK signaling has been defined. In this study, we demonstrate that Sprouty (Spry) is a possible target of Shp2. Spry acts as a conserved inhibitor of RTK signaling, and tyrosine phosphorylation of Spry is indispensable for its inhibitory activity. Shp2 was able to dephosphorylate fibroblast growth factor receptor-induced phosphotyrosines on Spry both in vivo and in vitro. Shp2-mediated dephosphorylation of Spry resulted in dissociation of Spry from Grb2. Furthermore, Shp2 could reverse the inhibitory effect of Spry on FGF-induced neurite outgrowth and MAP kinase activation. These findings suggest that Shp2 acts as a positive regulator in RTK signaling by dephosphorylating and inactivating Spry.