Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism
Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism
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DOI：
10.1038/ncb833
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发表时间：
2002-08-01
影响因子：
21.3
通讯作者：
Der, CJ
中科院分区：
文献类型：
--
作者：
Lambert, JM;Lambert, QT;Der, CJ
Rac是GTP酶Ras超家族的成员，并作为GDP/GTP调节开关发挥作用（1）。活性Rac-GTP的形成受到Dbl家族鸟嘌呤核苷酸交换因子（GEF）（如Tiam 1）的刺激（参考文献2）。一旦被激活，Rac刺激调节肌动蛋白组织、基因表达和细胞增殖的信号通路。Rac还在Ras癌蛋白下游的途径中发挥作用，这些途径刺激膜皱褶（3）、生长转化（4，5）、c-Jun氨基末端激酶（JNK）促分裂原活化蛋白激酶的活化（6）、NF-κ B转录因子的活化和促进细胞存活（7，8）。虽然最近的研究支持磷脂酰肌醇3-OH激酶（PI（3）K）依赖性机制，Ras可能通过该机制激活Rac（参考文献9，10），但确切的机制仍有待确定。在这里，我们证明Tiam 1，一个Rac特异性GEF，优先与激活的GTP结合Ras通过Ras结合结构域。此外，激活的Ras和Tiam 1协同作用，以PI（3）K非依赖性方式引起Rac-GTP的协同形成。因此，Tiam 1可以作为效应子直接介导Ras激活Rac。
Rac is a member of the Ras superfamily of GTPases and functions as a GDP/GTP-regulated switch(1). Formation of active Rac-GTP is stimulated by Dbl family guanine nucleotide exchange factors (GEFs), such as Tiam1 (ref. 2). Once activated, Rac stimulates signalling pathways that regulate actin organization, gene expression and cellular proliferation. Rac also functions downstream of the Ras oncoprotein in pathways that stimulate membrane ruffling(3), growth transformation(4,5), activation of the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase(6), activation of the NF-kappaB transcription factor and promotion of cell survival(7,8). Although recent studies support phosphatidylinositol 3-OH kinase (PI( 3) K)-dependent mechanisms through which Ras might activate Rac (refs 9,10), the precise mechanism remains to be determined. Here we demonstrate that Tiam1, a Rac-specific GEF, preferentially associates with activated GTP-bound Ras through a Ras-binding domain. Furthermore, activated Ras and Tiam1 cooperate to cause synergistic formation of Rac-GTP in a PI( 3) K-independent manner. Thus, Tiam1 can function as an effector that directly mediates Ras activation of Rac.