The Rac-cGMP Signaling Pathway

描述（申请人提供）：该项目的长期目标是了解新发现的Rac-cGMP途径的信号传导机制和生理功能。许多膜信号受体可以增加普遍存在的第二信使环 GMP (cGMP) 的细胞水平。然而，这些膜信号受体增加 cGMP 的分子机制尚不清楚。我们最近发现了一种新的 Rac-cGMP 信号通路。小 G 蛋白 Rac 使用其效应器 PAK（p21 激活激酶）以变构方式激活跨膜鸟苷酸环化酶 (GC)。这些发现揭示了多种信号受体通过 cGMP 调节生理反应的一般机制。尽管需要 PAK 的激酶活性，但 PAK 并不直接磷酸化 GC。相反，PAK 需要自身磷酸化来维持其激活构型。然后，PAK 的活性形式以变构方式激活跨膜 GC。本申请的主要重点是 Rac 通过其效应子 PAK 调节跨膜鸟苷酸环化酶活性的生化机制。我们将在特定目标 1 中研究 PAK 对跨膜鸟苷酸环化酶的变构激活。在特定目标 2 中，我们将探索 cGMP 下游的信号分子。我们将在具体目标 3 中研究 Rac-cGMP 途径的生理功能。 公共卫生相关性：这项研究与人类健康直接相关。 Rac GTPase 和第二信使 cGMP 都是许多生理功能的关键调节因子。细胞迁移和血管通透性对于血管发育至关重要，并与心血管疾病有关。 Rac-cGMP 通路的信号传导机制和生理功能的研究将显着增进我们对心血管功能和疾病的理解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This research is directly related to human health. Both Rac GTPase and the second messenger cGMP are critical regulators of many physiological functions. Cell migration and vascular permeability are essential for vascular development and are involved in cardiovascular diseases. Investigations of the signaling mechanisms and physiological functions of the Rac-cGMP pathway will significantly advance our understanding of cardiovascular function and diseases.