Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI
Diacylglycerol kinase α mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI
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DOI：
10.1073/pnas.0908326107
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发表时间：
2010-03-02
影响因子：
11.1
通讯作者：
Graziani, Andrea
中科院分区：
文献类型：
--
作者：
Chianale, Federica;Rainero, Elena;Graziani, Andrea
二酰基甘油激酶（DGKs）将二酰基甘油（DAG）转化为磷脂酸（PA），作为DAG和PA介导的信号传导之间的分子开关。我们之前通过控制Rac小gtpase激活和质膜定位发现，src依赖的激活和DGK α的质膜募集是生长因子诱导的细胞迁移和褶皱所必需的。本文揭示了DGK α协调Rac定位的信号通路。我们发现，在肝细胞生长因子刺激下，DGK α通过产生PA，提供一个关键信号，在集落生长上皮细胞的皱襞部位与RhoGDI和Rac复合物募集非典型PKC zeta/iota （aPKC zeta/iota）。然后，DGK α依赖的aPKC zeta/iota激活介导Rac从RhoGDI抑制复合物中释放，使其激活并导致膜褶的形成，这是细胞迁移的必要条件。这些发现强调DGK α是连接酪氨酸激酶生长因子受体调节aPKCs和RhoGDI的脂质信号通路的中心元件，并提供调节Rac与质膜关联的位置信号。
Diacylglycerol kinases (DGKs) convert diacylglycerol (DAG) into phosphatidic acid (PA), acting as molecular switches between DAG- and PA-mediated signaling. We previously showed that Src-dependent activation and plasma membrane recruitment of DGK alpha are required for growth-factor-induced cell migration and ruffling, through the control of Rac small-GTPase activation and plasma membrane localization. Herein we unveil a signaling pathway through which DGK alpha coordinates the localization of Rac. We show that upon hepatocyte growth-factor stimulation, DGK alpha, by producing PA, provides a key signal to recruit atypical PKC zeta/iota (aPKC zeta/iota) in complex with RhoGDI and Rac at ruffling sites of colony-growing epithelial cells. Then, DGK alpha-dependent activation of aPKC zeta/iota mediates the release of Rac from the inhibitory complex with RhoGDI, allowing its activation and leading to formation of membrane ruffles, which constitute essential requirements for cell migration. These findings highlight DGK alpha as the central element of a lipid signaling pathway linking tyrosine kinase growth-factor receptors to regulation of aPKCs and RhoGDI, and providing a positional signal regulating Rac association to the plasma membrane.