The Rac-cGMP Signaling Pathway

描述(申请人提供)：本项目的长期目标是了解新发现的Rac-cGMP途径的信号机制和生理功能。许多膜信号受体可以增加细胞中普遍存在的第二信使环GMP(CGMP)的水平。然而，这些膜信号受体增加cGMP的分子机制尚不清楚。我们最近发现了一条新的RAC-cGMP信号通路。小G蛋白Rac利用其效应蛋白PAK(p21激活的激酶)变构激活跨膜鸟苷酸环化酶(GCs)。这些发现揭示了不同信号受体通过cGMP调节生理反应的一般机制。虽然PAK的活性是必需的，但PAK并不直接使GC磷酸化。相反，需要PAK的自动磷酸化来维持其激活的配置。然后，活性形式的PAK变构激活跨膜GC。这一应用的主要焦点是RAC通过其效应器PAK调节跨膜鸟苷酸环化酶活性的生化机制。在特定目标1中，我们将研究PAK对跨膜鸟酰环化酶的变构激活作用。在特定目标2中，我们将探索cGMP下游的信号分子。我们将在特定的目标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 GTP酶和第二信使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是血管发育所必需的，与心血管疾病密切相关。研究Rac-cGMP通路的信号机制和生理功能将极大地促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.