Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway
Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCα in a Rac1 activation pathway
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DOI：
10.1083/jcb.200810179
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发表时间：
2009-07-13
影响因子：
7.8
通讯作者：
Simons, Michael
中科院分区：
文献类型：
--
作者：
Elfenbein, Arye;Rhodes, John M.;Simons, Michael
成纤维细胞生长因子 2 (FGF2) 是发育、病理和治疗性血管生成的主要调节因子。其活性部分是通过与蛋白聚糖受体 Syndecan 4 (S4) 结合来介导的。血管生成需要小鸟苷三磷酸酶 Rac1 的极化激活，这涉及 RhoGDI1 的局部解离以及与质膜的结合。先前的研究表明，S4 或其衔接蛋白 Synectin 的基因缺失会导致 Rac 激活去极化、内皮迁移减少和其他生理缺陷。在这项研究中，我们表明 S4 下游的 Rac1 激活是由 RhoG 激活途径介导的。 RhoG 通过 RhoGDI1 维持非活性状态，RhoGDI1 存在于与 Synectin 和 S4 的三元复合物中。 S4 与 Synectin 的结合增加了后者与 RhoGDI1 的结合，从而增强了 RhoGDI1 对 RhoG 的亲和力。 S4 聚类激活 PKC α，从而磷酸化 RhoGDI1 Ser(96)。这种磷酸化会触发 RhoG 的释放，从而导致 Rac1 的极化激活。因此，FGF2 诱导的 Rac1 激活取决于先前未表征的三元 S4-synectin-RhoGDI1 蛋白复合物对 RhoG 的抑制以及通过 PKC α 的激活。
Fibroblast growth factor 2 (FGF2) is a major regulator of developmental, pathological, and therapeutic angiogenesis. Its activity is partially mediated by binding to syndecan 4 (S4), a proteoglycan receptor. Angiogenesis requires polarized activation of the small guanosine triphosphatase Rac1, which involves localized dissociation from RhoGDI1 and association with the plasma membrane. Previous work has shown that genetic deletion of S4 or its adapter, synectin, leads to depolarized Rac activation, decreased endothelial migration, and other physiological defects. In this study, we show that Rac1 activation downstream of S4 is mediated by the RhoG activation pathway. RhoG is maintained in an inactive state by RhoGDI1, which is found in a ternary complex with synectin and S4. Binding of S4 to synectin increases the latter's binding to RhoGDI1, which in turn enhances RhoGDI1's affinity for RhoG. S4 clustering activates PKC alpha, which phosphorylates RhoGDI1 at Ser(96). This phosphorylation triggers release of RhoG, leading to polarized activation of Rac1. Thus, FGF2-induced Rac1 activation depends on the suppression of RhoG by a previously uncharacterized ternary S4-synectin-RhoGDI1 protein complex and activation via PKC alpha.