The Rac-cGMP Signaling Pathway

项目描述 本项目的长期目标是了解信号机制 以及新发现的Rac-cGMP通路的生理功能。许多 膜信号受体可以增加细胞水平的普遍存在的 第二信使环GMP（cGMP）。然而， 这些膜信号受体增加cGMP是未知的。我们 最近发现了一种新的Rac-cGMP信号通路。小G蛋白 Rac使用其效应子PAK（p21激活激酶）变构激活 跨膜鸟苷酸环化酶（GC）。这些发现揭示了一种普遍的 不同信号受体调节生理反应的机制 通过cGMP。虽然PAK的激酶活性是必需的，但PAK不 直接磷酸化GC。相反，需要PAK的自磷酸化， 保持其激活配置。PAK的活性形式然后变构 激活跨膜GC。此应用程序的主要重点是 Rac通过其效应子PAK调节细胞凋亡的生化机制。 跨膜鸟苷酸环化酶的活性。我们将研究变构 在特异性Aim 1中通过PAK激活跨膜鸟苷酸环化酶。在 具体目标2，我们将探索cGMP下游的信号分子。 我们将研究Rac-cGMP通路在细胞中的生理功能。 具体目标3。

Project Description The long-term objective of this project is to understand the signaling mechanisms and physiological functions of the newly discovered Rac-cGMP pathway. Many membrane-signaling receptors can increase the cellular levels of the ubiquitous second messenger cyclic GMP (cGMP). However, the molecular mechanism by which these membrane-signaling receptors increased cGMP was not known. We recently uncovered a new Rac-cGMP signaling pathway. The small G protein Rac uses its effector PAK (p21-activated kinase) to allosterically activate transmembrane guanylyl cyclases (GCs). These findings reveal a general mechanism for diverse signaling receptors to modulate physiological responses through cGMP. Although the kinase activity of PAK is required, PAK does not directly phosphorylate GCs. Instead, autophosphorylation of PAK is needed to maintain its activated configuration. The active form of PAK then allosterically activates transmembrane GCs. The main focus of this application is on the biochemical mechanism by which Rac, through its effector PAK, regulates the activity of transmembrane guanylyl cyclases. We will investigate the allosteric activation of transmembrane guanylyl cyclases by PAK in the Specific Aim 1. In the Specific Aim 2, we will explore the signaling molecules downstream of cGMP. We will investigate the physiological function of the Rac-cGMP pathway in the Specific Aim 3.