摘要
异源三聚体G蛋白(Heterotrimeric G-Proteins)是非常关键的细胞信号转导因子。除了传导来自G蛋白偶联受体(G Protein-Coupled Receptors, GPCRs)的信号以外,异源三聚体G蛋白还能介导很多来自非G蛋白偶联受体的生理功能。之前我们研究小组已经证明一个异源三聚体G蛋白的成员,Gα13,是生长因子受体诱导的细胞肌动蛋白骨架重分布过程,如环状细胞膜波皱(Dorsal Ruffle)形成和消失以及细胞迁移所必需的。Gα13所介导的环状膜波皱形成和细胞迁移等生理过程是由生长因子激活受体酪氨酸激酶(Receptor Tyrosine Kinases, RTKs)所诱导的,不依赖于G蛋白偶联受体。然而,受体酪酸激酶将信号传导到Gα13的机制尚不清楚。
这里我们证明Ric-8A蛋白,一个某些异源三聚体G蛋白的非受体的鸟苷酸交换因子(Guanine Nucleotide Exchange Factor, GEF),在连接受体酪氨酸激酶和Gα13之间起到了关键作用。利用RNA干扰实现的Ric-8A蛋白表达水平的下调减慢了血小板衍生生长因子(Platelet-Derived Growth Factor, PDGF)所诱导的细胞环状膜波皱的形成、消失,以及细胞迁移。血小板衍生生长因子能够刺激细胞内Ric-8A蛋白的活性。并且纯化的Ric-8A蛋白能够与纯化的Gα13蛋白以一种依赖于鸟苷酸结合状态的方式直接相互作用。Ric-8A的缺失阻碍了Gα13的正常膜转运。因此Ric-8A在生长因子诱导的细胞骨架蛋白重分布中起着非常关键的作用。
我们还研究了Gα13与Ab1之间的相互作用机制,以及它们的相互作用对于细胞肌动蛋白骨架和细胞迁移的重要作用。我们的研究揭示了两种蛋白之间的相互作用位点,以及当它们的相互作用被抑制时肌动蛋白重分布、细胞膜波皱的消失和细胞迁移等细胞生理过程都受到影响。这可能为解释细胞迁移过程的调控提供思路。
Heterotrimeric G proteins are critical transducers of cellular signaling. In addition to their classic roles in relaying signals from G protein-coupled receptors (GPCRs), heterotrimeric G proteins also mediate physiological functions from non-GPCRs. Previously we have shown that Gα13, a member of the heterotrimeric G proteins, is essential for growth factor receptor-induced actin cytoskeletal reorganization such as dynamic dorsal ruffle turnover and cell migration. These Gα13-mediated dorsal ruffle turnover and cell migration by growth factors acting on their receptor tyrosine kinases (RTKs) are independent of GPCRs. However, the mechanism by which RTKs signal to Gα13is not known. Here we show that Ric-8A, a non-receptor guanine nucleotide exchange factor for some heterotrimeric G proteins, is critical for coupling RTKs to Gα13. Down-regulation of Ric-8A protein levels in cells by RNA interference slowed down platelet-derived growth factor (PDGF)-induced dorsal ruffle turnover and inhibited PDGF-initiated cell migration. PDGF was able to increase the activity of Ric-8A in cells. Furthermore, purified Ric-8A proteins directly interact with purified Gα13protein in a nucleotide-dependent manner. Deficiency of Ric-8A prevented the membrane translocation of Gα13. Hence, Ric-8A is critical for growth factor receptor-induced actin cytoskeletal reorganization.
We also studied the interaction mechanism of Gα13and the tyrosine kinase Abl and the role of this interaction in cytoskeleton reorganization and cell migration. Inhibition of this interaction affected both dorsal ruffle turn over and cell migration. Both Gα13and Abl are important regulator of actin cytoskeleton and cell migration, but their function may be different, or even opposite. The novel interaction we described here may shed light on how do they coordinate each other and regulate cell migration together.
引文
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