Cytoskeletal reorganization by G protein-coupled receptors is dependent on phosphoinositide 3-kinase γ, a Rac guanosine exchange factor, and Rac
Cytoskeletal reorganization by G protein-coupled receptors is dependent on phosphoinositide 3-kinase γ, a Rac guanosine exchange factor, and Rac
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DOI：
10.1128/mcb.18.8.4744
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发表时间：
1998-08-01
影响因子：
5.3
通讯作者：
Abrams, CS
中科院分区：
文献类型：
--
作者：
Ma, AD;Metjian, A;Abrams, CS
肌动蛋白骨架的重组是细胞对各种细胞外信号的早期反应。虽然G蛋白偶联受体的刺激也会导致细胞骨架的改变，但对肌动蛋白重排的途径的解剖主要集中在生长因子受体或整合素启动的途径上。在转染的Cos-7SH细胞中，化学引诱剂甲酰基肽受体的激活诱导皮质肌动蛋白聚合和中央肌动蛋白束数量的减少。在本报告中，我们发现细胞骨架重组可以通过G蛋白β γ异二聚体（G(β γ)）、磷酸肌苷3-激酶γ (PI3-K- γ)、Rac的鸟苷交换因子（GEF）和Rac进行转导。PI3-K γ、Rac GEF Vav或Rac的失活变体的表达可阻断肌动蛋白重排。PI3-K的药理学抑制剂wortmannin和LY294002都不能抑制组成活性pac诱导的肌动蛋白重排。Vav显性阴性变体对细胞骨架重组的抑制可以通过组成活性Rac的共表达来恢复。相比之下，即使没有PI3-K γ的刺激，缺少pleckstrin同源性（PH）结构域的Vav变体也会诱导JNK激活并导致细胞骨架重组。这表明Vav的PH结构域控制着Vav的鸟苷交换活性，可能是由PI3-K产生的D3磷酸肌苷调节的机制。综上所述，这些发现描绘了一条从G蛋白偶联受体激活到肌动蛋白重组的途径，该途径依次涉及G（β - γ）、p13 - k - γ、Rac GEF和Rac。
Reorganization of the actin cytoskeleton is an early cellular response to a variety of extracellular signals. Dissection of pathways leading to actin rearrangement has focused largely on those initiated by growth factor receptors or integrins, although stimulation of G protein-coupled receptors also leads to cytoskeletal changes. In transfected Cos-7SH cells, activation of the chemoattractant formyl peptide receptor induces cortical actin polymerization and a decrease in the number of central actin bundles. In this report, we show that cytoskeletal reorganization can be transduced by G protein beta gamma heterodimers (G(beta gamma)), phosphoinositide 3-kinase gamma (PI3-K-gamma), a guanosine exchange factor (GEF) for Rac, and Rac, Expression of inactive variants of either PI3-K gamma, the Rac GEF Vav, or Rac blocked the actin rearrangement. Neither wortmannin nor LY294002, pharmacologic inhibitors of PI3-K, could inhibit the actin rearrangement induced by a constitutively active pac. The inhibition of cytoskeletal reorganization by the dominant negative Vav variants could be rescued by coexpression of a constitutively active form of Rac. In contrast, a Vav variant with its pleckstrin homology (PH) domain missing constitutively induced JNK activation and led to cytoskeletal reorganization, even without stimulation by PI3-K gamma. This suggests that the PH domain of Vav controls the guanosine exchange activity of Vav, perhaps by a mechanism regulated by D3 phosphoinositides generated by PI3-K. Taken together, these findings delineate a pathway leading from activation of a G protein coupled receptor to actin reorganization which sequentially involves G(beta gamma), P13-K-gamma, a Rac GEF, and Rac.