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首页> 外文期刊>Cellular Signalling >RhoGEF17, a Rho-specific guanine nucleotide exchange factor activated by phosphorylation via cyclic GMP-dependent kinase Iα
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RhoGEF17, a Rho-specific guanine nucleotide exchange factor activated by phosphorylation via cyclic GMP-dependent kinase Iα

机译：RhoGEF17，Rho特异性鸟嘌呤核苷酸交换因子，通过依赖环GMP的激酶Iα磷酸化激活

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摘要

RhoGEF17, the product of the ARHGEF17 gene, is a Rho-specific guanine nucleotide exchange factor (GEF) with an unusual structure and so far unknown function. In order to get insights in its regulation, we studied a variety of signaling pathways for activation of recombinantly expressed RhoGEF17. We found that in the presence of stable cGMP analogs RhoGEF17 associates with and is phosphorylated by co-expressed cGKIα at distinct phosphorylation sites leading to a cooperative activation of RhoA, the Rho dependent kinases (ROCK) and serum response factor-induced gene transcription. Activation of protein kinase A did not induce phosphorylation of RhoGEF17 nor altered its activity. Furthermore, we obtained evidence for a ROCK-driven positive feedback mechanism involving serine/threonine protein phosphatases, which further enhanced cGMP/cGKIα-induced RhoGEF17 activation. By using mutants of RhoA which are phosphorylation resistant to cGK or mimic phosphorylation at serine 188, we could show that RhoGEF17 is able to activate RhoA independently of its phosphorylation state. Together with the ROCK-enforced activation of RhoGEF17 by cGMP/cGKIα, this might explain why expression of RhoGEF17 switches the inhibitory effect of cGMP/cGKIα on serum-induced RhoA activation into a stimulatory one. We conclude that RhoGEF17, depending on its expression profile and level, might drastically alter the effect of cGMP/cGK involving signaling pathways on RhoA-activated downstream effectors.
机译：RhoGEF17是ARHGEF17基因的产物，是一种Rho特异性鸟嘌呤核苷酸交换因子（GEF），具有异常的结构和迄今未知的功能。为了深入了解其调控，我们研究了多种信号通路来激活重组表达的RhoGEF17。我们发现，在稳定的cGMP类似物存在下，RhoGEF17在不同的磷酸化位点与共表达的cGKIα缔合并被其磷酸化，从而导致RhoA，Rho依赖激酶（ROCK）和血清反应因子诱导的基因转录的协同激活。蛋白激酶A的激活不会诱导RhoGEF17的磷酸化，也不会改变其活性。此外，我们获得了包含丝氨酸/苏氨酸蛋白磷酸酶的ROCK驱动的正反馈机制的证据，该机制进一步增强了cGMP /cGKIα诱导的RhoGEF17激活。通过使用对cGK具有磷酸化抗性或在丝氨酸188上具有模拟磷酸化作用的RhoA突变体，我们可以证明RhoGEF17能够独立于其磷酸化状态激活RhoA。连同cGMP /cGKIα的ROCK激活的RhoGEF17激活，这可以解释为什么RhoGEF17的表达将cGMP /cGKIα对血清诱导的RhoA激活的抑制作用转变为一种刺激性作用。我们得出的结论是，RhoGEF17取决于其表达谱和水平，可能会大大改变cGMP / cGK的作用，其中涉及RhoA激活的下游效应子的信号传导途径。

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