Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck
Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck
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DOI：
10.1016/s0960-9822(06)00052-2
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发表时间：
1997-02-01
期刊：
影响因子：
9.2
通讯作者：
Mayer, BJ
中科院分区：
文献类型：
--
作者：
Lu, WG;Katz, S;Mayer, BJ
背景：衔接蛋白Nck由三个Src同源3（SH 3）结构域和一个SH 2结构域组成。与Grb 2衔接蛋白（已知其将受体酪氨酸激酶偶联至小GT3 Ras的活化）一样，推测Nck使用其SH 2结构域与酪氨酸磷酸化蛋白结合，并使用其SH 3结构域与下游效应蛋白结合。然而，关于NCK的特定生物学功能知之甚少。Pak家族的丝氨酸/苏氨酸激酶被激活的GTP结合形式的Cdc 42或拉德，这是小GTP酶的Rho家族参与调节的肌动蛋白cytokerelastics.Results的组织的结合：我们目前的证据表明，NCK可以介导的重新定位和随后的激活的Pak 1激酶。我们表明，NCK协会在体内与Pak使用其三个SH 3结构域的第二个，和本地化的这个单独的NCK SH 3结构域，或Pak激酶本身，到膜的结果在激活Pak和刺激下游促分裂原活化蛋白激酶级联。结论：Pak 1的失活突变体可阻断Nck SH 3结构域对下游信号的激活作用。结论：Pak 1在细胞膜上的定位在没有其他信号的情况下就足以激活Nck SH 3结构域，提示Nck接头蛋白可将细胞蛋白酪氨酸磷酸化的变化与Cdc 42/Pak信号通路联系起来。
Background: The adaptor protein Nck consists of three Src homology 3 (SH3) domains followed by one SH2 domain. Like the Grb2 adaptor protein, which is known to couple receptor tyrosine kinases to the activation of the small GTPase Ras, Nck is presumed to bind to tyrosine-phosphorylated proteins using its SH2 domain and to downstream effector proteins using its SH3 domain. Little is known, however, about the specific biological function of Nck. The Pak family of serine/threonine kinases are known to be activated by binding to the GTP-bound form of Cdc42 or Rad, which are small GTPases of the Rho family that are involved in regulating the organization of the actin cytoskeleton.Results: We present evidence that Nck can mediate the relocalization and subsequent activation of the Pak1 kinase. We show that Nck associates in vivo with Pak using the second of its three SH3 domains, and that localization of this individual Nck SH3 domain, or of Pak kinase itself, to the membrane results in activation of Pak and stimulation of downstream mitogen activated protein kinase cascades. Activation of downstream signaling by the membrane-localized Nck SH3 domain is blocked by a kinase-inactive mutant form of Pak1.Conclusion: These results demonstrate that localization of Pak1 to the membrane in the absence of other signals is sufficient for its activation, and imply that the Nck adaptor protein could function to link changes in tyrosine phosphorylation of cellular proteins to the Cdc42/Pak signaling pathway.