Potent activation of RhoA by Gαq and Gq-coupled receptors
Potent activation of RhoA by Gαq and Gq-coupled receptors
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DOI：
10.1074/jbc.m204715200
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发表时间：
2002-07-26
影响因子：
4.8
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Chikumi, H;Vázquez-Prado, J;Gutkind, JS
G(i)、G(s) 和 G(q) 家族的异三聚体 G 蛋白主要通过调节关键细胞内第二信使生成系统的活性来控制多种生理功能。然而，G(12) 家族的亚基 Galpha(12) 和 Galpha(13) 可以促进独立于传统第二信使的细胞反应，而是由 Rho 家族的小 GTP 结合蛋白及其下游靶标的激活引起的。这些发现导致了鸟嘌呤核苷酸交换因子 (GEF) 的一个新家族的鉴定，该家族提供了 Galpha(12/13) 和 Rho 刺激之间的直接联系。最近的观察表明，Galpha(q) 及其偶联受体引发的许多细胞反应也需要 Rho 的功能活性。然而，现有证据表明 Gaq 可能作用于 Rho 下游的通路，而不是促进 Rho 激活。这些看似相互矛盾的观察结果以及最近开发的用于评估活性 Rho 体内水平的敏感测定法促使我们思考 Gaq 及其偶联受体是否可以刺激内源性 Rho。在这里，我们表明，激活形式的 Gaq 的表达以及对 G(q) 偶联受体或响应 G(i) 连接受体的嵌合 Galpha(q) 分子的刺激可以促进 HEK-293T 细胞中内源性 Rho 的强烈激活。有趣的是，这种反应并没有被干扰 G a, 刺激其连接的 RhoGEF 能力的分子所阻止，这表明存在一种新的分子机制，Gaq 和 G(q) 偶联受体大家族可以通过该机制调节 Rho 及其下游信号传导通路的活性。
Heterotrimeric G proteins of the G(i), G(s), and G(q) family control a wide array of physiological functions primarily by regulating the activity of key intracellular second messenger-generating systems. a subunits of the G(12) family, Galpha(12) and Galpha(13), however, can promote cellular responses that are independent of conventional second messengers but that result from the activation of small GTP-binding proteins of the Rho family and their downstream targets. These findings led to the identification of a novel family of guanine-nucleotide exchange factors (GEFs) that provides a direct link between Galpha(12/13) and Rho stimulation. Recent observations suggest that many cellular responses elicited by Galpha(q) and its coupled receptors also require the functional activity of Rho. However, available evidence suggests that Gaq may act on pathways downstream from Rho rather than by promoting Rho activation. These seemingly conflicting observations and the recent development of sensitive assays to assess the in vivo levels of active Rho prompted us to ask whether Gaq and its coupled receptors can stimulate endogenous Rho. Here we show that the expression of activated forms of Gaq and the stimulation of G(q)-coupled receptors or chimeric Galpha(q) molecules that respond to G(i)-linked receptors can promote a robust activation of endogenous Rho in HEK-293T cells. Interestingly, this response was not prevented by molecules interfering with the ability of G a,, to stimulate its linked RhoGEFs, together suggesting the existence of a novel molecular mechanism by which Gaq and the large family of G(q)-coupled receptors can regulate the activity of Rho and its downstream signaling pathways.