Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.
Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1.
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DOI：
10.1083/jcb.200206079
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发表时间：
2003-01-06
期刊：
影响因子：
--
通讯作者：
Scita G
中科院分区：
文献类型：
--
作者：
Innocenti M;Frittoli E;Ponzanelli I;Falck JR;Brachmann SM;Di Fiore PP;Scita G
I类磷酸肌肽3-激酶（pi3k）参与许多由受体酪氨酸激酶（rtk）控制的细胞反应，包括肌动蛋白细胞骨架重塑。在这一途径中，Rac是PI3K的关键下游靶点/效应物。然而，信号如何从PI3K路由到Rac尚不清楚。这种功能的一个可能的候选者是rac激活复合物Eps8-Abi1-Sos-1，它具有rac特异性鸟嘌呤核苷酸交换因子（GEF）活性。在这里，我们发现Abi1（也称为E3b1）通过p85将PI3K招募到一个包括Eps8和Sos-1的多分子信号复合体中。p85被募集到Eps8-Abi1-Sos-1复合物和PI3K的催化产物磷脂酰肌醇3,4,5磷酸（PIP3）上，共同揭示了其体外Rac-GEF活性。此外，它们对于激活Rac和Rac依赖的肌动蛋白重塑是必不可少的。在生长因子刺激下，内源性p85和Abi1一致地共定位到膜褶，缺乏p85的细胞不能支持Abi1依赖性Rac激活。我们的研究结果定义了一种机制，即信号的传播，源自rtk或Ras并导致肌动蛋白重组，由PI3K和rac特异性GEF复合物之间的直接物理相互作用控制。
Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is unclear. One possible candidate for this function is the Rac-activating complex Eps8–Abi1–Sos-1, which possesses Rac-specific guanine nucleotide exchange factor (GEF) activity. Here, we show that Abi1 (also known as E3b1) recruits PI3K, via p85, into a multimolecular signaling complex that includes Eps8 and Sos-1. The recruitment of p85 to the Eps8–Abi1–Sos-1 complex and phosphatidylinositol 3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concur to unmask its Rac-GEF activity in vitro. Moreover, they are indispensable for the activation of Rac and Rac-dependent actin remodeling in vivo. On growth factor stimulation, endogenous p85 and Abi1 consistently colocalize into membrane ruffles, and cells lacking p85 fail to support Abi1-dependent Rac activation. Our results define a mechanism whereby propagation of signals, originating from RTKs or Ras and leading to actin reorganization, is controlled by direct physical interaction between PI3K and a Rac-specific GEF complex.
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DOI：
10.1083/jcb.200108035
发表时间：
2002-01-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Innocenti M;Tenca P;Frittoli E;Faretta M;Tocchetti A;Di Fiore PP;Scita G
通讯作者：
Scita G
影响因子：
11.4
作者：
Mongiovi, AM;Romano, PR;Di Fiore, PP
通讯作者：
Di Fiore, PP
影响因子：
56.9
作者：
Nimnual, AS;Yatsula, BA;Bar-Sagi, D
通讯作者：
Bar-Sagi, D
影响因子：
4.1
作者：
Fleming, IN;Gray, A;Downes, CP
通讯作者：
Downes, CP
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L