Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin
Regulation of p70 S6 kinase by complex formation between the rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin
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DOI：
10.1074/jbc.m207876200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Feig, LA
中科院分区：
文献类型：
--
作者：
Buchsbaum, RJ;Connolly, BA;Feig, LA
Tiam 1是一种普遍存在的鸟嘌呤核苷酸交换因子（GEF），可激活Rac GT3。我们之前已经表明，Tiam 1的N末端通过与IB 2（一种促进Rac激活p38激酶级联的支架）的结合，有助于其下游靶点Rac的信号传导特异性。在这里，我们表明，Tiam 1的N末端可以影响Rac信号转导特异性以不同的方式与spinophilin，支架结合到P70 S6激酶，另一种蛋白质调控的Rac的相互作用。特别是，spinophilin结合促进Tiam 1的质膜定位，并增强Tiam 1激活p70 S6激酶的能力。相反，亲棘素结合抑制Tiam激活Pak 1（一种不同的Rac效应子）的能力。最后，不能结合Tiam 1的突变体spinophilin抑制细胞中血清诱导的p70 S6激酶活化，表明Tiam 1/spinophilin复合物有助于通过细胞外信号调节p70 S6激酶。这些发现增加了越来越多的证据支持以下概念：一些Rac-GEF不仅激活Rac GTP酶，而且通过结合与特定Rac效应子途径的组分复合的特定支架来参与Rac效应子的选择。
Tiam1 is a ubiquitous guanine nucleotide exchange factor (GEF) that activates the Rac GTPase. We have shown previously that the N terminus of Tiam1 contributes to the signaling specificity of its downstream target Rac via association with IB2, a scaffold that promotes Rac activation of a p38 kinase cascade. Here we show that the N terminus of Tiam1 can influence Rac signaling specificity in a different way by interaction with spinophilin, a scaffold that binds to p70 S6 kinase, another protein regulated by Rac. In particular, spinophilin binding promotes the plasma membrane localization of Tiam1 and enhances the ability of Tiam1 to activate p70 S6 kinase. In contrast, spinophilin binding suppresses the ability of Tiam to activate Pak1, a different Rac effector. Finally, a mutant spinophilin that cannot bind to Tiam1 suppresses serum-induced p70 S6 kinase activation in cells, suggesting that a Tiam1/spinophilin complex contributes to p70 S6 kinase regulation by extracellular signals. These findings add to a growing body of evidence supporting the concept that some Rac-GEFs not only activate Rac GTPases but also participate in the selection of Rac effector by binding to particular scaffolds that complex with components of specific Rac effector pathways.