Ras-independent activation of Ral by a Ca2+-dependent pathway
Ras-independent activation of Ral by a Ca2+-dependent pathway
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DOI：
10.1016/s0960-9822(98)70327-6
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发表时间：
1998-07-02
期刊：
影响因子：
9.2
通讯作者：
Martin, GS
中科院分区：
文献类型：
--
作者：
Hofer, F;Berdeaux, R;Martin, GS
Rala和RalB蛋白组成一个不同的小GTP酶家族[1]。RalGDS、RLF和Rgl等Ral特异性鸟嘌呤核苷酸交换因子与激活的RAS相互作用，并在小鼠成纤维细胞的转化过程中与RAS协同作用[2-5]。因此，RalGDS与RAS的相互作用及其随后的激活被认为构成了一条不同的RAS依赖的信号通路。黄递素的功能在很大程度上是未知的。有间接证据表明，Ral可能通过与RIP1(也称为RLIP或RalBP1)的相互作用来调节细胞骨架的功能，RIP1是小GTP酶CDC42和Rac[6-8]的特异性GTP激活蛋白，Ral还与磷脂酶D(PLD)结合，因此可能通过磷脂发挥作用[9]，我们检测了不同有丝分裂原刺激的大鼠-2成纤维细胞中激活的、GTP结合的Ral(Ral-GTP)的内源性水平。溶血磷脂酸(LPA)和表皮生长因子(EGF)同时激活RAS依赖和RAS非依赖的信号通路[10，11]，快速激活RAL。然而，显性负性RAS(S17N)或百日咳毒素抑制RAS激活对RAL-GTP水平影响不大。钙离子载体离子载体离子霉素可激活Ral，磷脂酶C(PLC)抑制剂可阻断LPA或EGF的激活。本研究结果证实了细胞内钙离子依赖的激活机制。
The RalA and RalB proteins comprise a distinct family of small GTPases [1]. Ral-specific guanine nucleotide exchange factors such as RalGDS, Rlf and RGL interact with activated Ras and cooperate with Ras in the transformation of murine fibroblasts [2-5]. Thus, the interaction of RalGDS with Ras and the subsequent activation of Ral are thought to constitute a distinct Ras dependent signaling pathway. The function of Ral is largely unknown. There is circumstantial evidence that Ral may have a function in regulating the cytoskeleton through its interaction with RIP1 (also known as RLIP or RalBP1), a GTPase-activating protein specific for the small GTPases Cdc42 and Rac [6-8], Ral also binds to phospholipase D (PLD) and thus may play a role in signaling through phospholipids [9], We have examined endogenous levels of activated, GTP-bound Ral (Ral-GTP) in Rat-2 fibroblasts stimulated with various mitogens. Lysophosphatidic acid (LPA) and epidermal growth factor (EGF), which activate both Ras-dependent and Ras-independent signaling pathways [10,11], rapidly activated Ral. Inhibition of Ras activation by dominant-negative Ras (Ras(S17N)) or pertussis toxin had little effect on Ral-GTP levels, however. Ral was activated by the Ca2+ ionophore ionomycin, and activation by LPA or EGF could be blocked by a phospholipase C (PLC) inhibitor. The results presented here demonstrate a Ca2+-dependent mechanism for the activation of Ral.