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首页> 外文期刊>Molecular and Cellular Biology >Cdc42 and Phosphoinositide 3-Kinase Drive Rac-Mediated Actin Polymerization Downstream of c-Met in Distinct and Common Pathways
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Cdc42 and Phosphoinositide 3-Kinase Drive Rac-Mediated Actin Polymerization Downstream of c-Met in Distinct and Common Pathways

机译：Cdc42和磷酸肌醇3-激酶驱动c-Met下游Rac介导的肌动蛋白聚合的独特途径。

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Activation of c-Met, the hepatocyte growth factor (HGF)/scatter factor receptor induces reorganization of the actin cytoskeleton, which drives epithelial cell scattering and motility and is exploited by pathogenic Listeria monocytogenes to invade nonepithelial cells. However, the precise contributions of distinct Rho-GTPases, the phosphatidylinositol 3-kinases, and actin assembly regulators to c-Met-mediated actin reorganization are still elusive. Here we report that HGF-induced membrane ruffling and Listeria invasion mediated by the bacterial c-Met ligand internalin B (InlB) were significantly impaired but not abrogated upon genetic removal of either Cdc42 or pharmacological inhibition of phosphoinositide 3-kinase (PI3-kinase). While loss of Cdc42 or PI3-kinase function correlated with reduced HGF- and InlB-triggered Rac activation, complete abolishment of actin reorganization and Rac activation required the simultaneous inactivation of both Cdc42 and PI3-kinase signaling. Moreover, Cdc42 activation was fully independent of PI3-kinase activity, whereas the latter partly depended on Cdc42. Finally, Cdc42 function did not require its interaction with the actin nucleation-promoting factor N-WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria invasion and membrane ruffling downstream of c-Met.
机译：肝细胞生长因子（HGF）/散射因子受体c-Met的激活诱导肌动蛋白细胞骨架的重组，从而驱动上皮细胞的散射和运动，并被致病性单核细胞增生李斯特菌侵袭非上皮细胞。然而，不同的Rho-GTP酶，磷脂酰肌醇3激酶和肌动蛋白组装调节剂对c-Met介导的肌动蛋白重组的精确贡献仍然难以捉摸。在这里我们报告说，由细菌c-Met配体internalin B（InlB）介导的HGF诱导的膜起皱和李斯特菌入侵显着受损，但在遗传去除Cdc42或磷酸肌醇3的药理抑制后并未消失-激酶（PI3-激酶）。虽然Cdc42或PI3激酶功能的丧失与HGF和InlB触发的Rac激活减少有关，但肌动蛋白重组和Rac激活的完全废除需要同时使Cdc42和PI3激酶信号传导同时失活。此外，Cdc42激活完全独立于PI3激酶活性，而后者部分依赖于Cdc42。最后，Cdc42功能不需要其与肌动蛋白成核促进因子N-WASP的相互作用。取而代之的是，肌动蛋白聚合反应是通过Rac下游的WAVE络合物通过Arp2 / 3络合物活化而驱动的。在一起，我们的数据建立了一个复杂的信号网络，其中包含作为关键分子的Cdc42和PI3-激酶，这些网络收敛于Rac介导的肌动蛋白重组，这对于 Listeria 入侵和c-Met下游的膜起皱至关重要。

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