CdGAP associates with actopaxin to regulate integrin-dependent changes in cell morphology and motility
CdGAP associates with actopaxin to regulate integrin-dependent changes in cell morphology and motility
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DOI：
10.1016/j.cub.2006.05.057
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发表时间：
2006-07-25
期刊：
影响因子：
9.2
通讯作者：
Turner, Christopher E.
中科院分区：
文献类型：
--
作者：
LaLonde, David P.;Grubinger, Markus;Turner, Christopher E.
背景资料：整合素信号传导，由细胞粘附到细胞外基质刺激，在协调细胞形态和迁移的变化中起关键作用。细胞骨架的必要重塑由Rho家族的小GTP酶控制，而小GTP酶又通过鸟嘌呤核苷酸交换因子（GEF）的激活和GTP酶激活蛋白（GAP）的失活来调节。然而，这些Rho GTthrombus调制器的精确的空间和时间调节的机制仍然知之甚少。结果：Cdc 42/Rac GAP CdGAP以前曾被牵连作为生长因子诱导的板状伪足形成的抑制剂。在本文中，CdGAP显示出定位于粘着斑，可能是通过其与actopaxin（桩蛋白和肌动蛋白结合蛋白）的氨基末端的直接缔合。CdGAP活性以粘附依赖性方式调节，并且通过野生型CdGAP和GAP缺陷突变体的过表达以及RNA干扰，显示出正常细胞铺展、极化板状伪足形成和细胞迁移所需。引入一个actopaxin突变体缺陷的CdGAP结合，或减少actopaxin通过使用RNAi，显着衰减这些effectues.Conclusions：我们已经建立了CdGAP是一个重要的调节整合素诱导的Rho家族信号转导的细胞骨架和它的相互作用与焦点粘附蛋白actopaxin是至关重要的正确的空间和/或时间调节CdGAP功能。对整合素与细胞外基质接合下游信号事件的协调的完整理解将为在诸如伤口修复、发展和肿瘤细胞转移的过程中调节细胞迁移提供有价值的见解。
Background: Integrin signaling, stimulated by cell adhesion to the extracellular matrix, plays a critical role in coordinating changes in cell morphology and migration. The requisite remodeling of the cytoskeleton is controlled by the Rho family of small GTPases, which are, in turn, regulated via activation by guanine-nucleotide exchange factors (GEFs) and inactivation by GTPase-activating proteins (GAPs). However, the mechanisms contributing to the precise spatial and temporal regulation of these Rho GTPase modulators remain poorly understood.Results: The Cdc42/Rac GAP CdGAP has previously been implicated as an inhibitor of growth-factor-induced lamellipodia formation. Herein, CdGAP is shown to localize to focal adhesions, potentially through its direct association with the amino terminus of actopaxin, a paxillin and actin binding protein. CdGAP activity is regulated in an adhesion-dependent manner and, through the overexpression of wild-type CdGAP and a GAP-deficient mutant, as well as RNA interference, is shown to be required for normal cell spreading, polarized lamellipodia formation, and cell migration. Introduction of an actopaxin mutant defective for CdGAP binding, or reduction of actopaxin by using RNAi, significantly attenuated these effects.Conclusions: We have established that CdGAP is an important regulator of integrin-induced Rho family signaling to the cytoskeleton and that its interaction with the focal-adhesion protein actopaxin is critical for the correct spatial and/or temporal regulation of CdGAP function. A complete understanding of the coordination of signaling events downstream of integrin engagement with the extracellular matrix will provide valuable insight into the regulation of cell migration during processes such as wound repair, development, and tumor cell metastasis.