The Rac-cGMP Signaling Pathway

Rac-cGMP 信号通路

• 批准号: 7939038
• 负责人: Xin-Yun Huang
• 金额: $ 8.45万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939038
• 关键词: Actins; Allosteric Regulation; Biochemical; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Catalytic Domain; Cyclic GMP; Cytoskeletal Modeling; Development; Disease; Figs - dietary; Guanosine Triphosphate Phosphohydrolases; Guanylate Cyclase; Hand; Health; Human; In Vitro; Investigation; Link; Mediating; Membrane; Molecular; Monomeric GTP-Binding Proteins; Pathway interactions; Phosphotransferases; Physiological; Physiological Processes; Protein Kinase; Receptor Signaling; Reporting; Research; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; System; Vascular Endothelial Growth Factors; Vascular Permeabilities; atrial natriuretic factor receptor A; cell motility; in vivo; mouse model; novel; p21 activated kinase; public health relevance; receptor; response; second messenger

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.

描述（由申请人提供）：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无处不在的第二信使循环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。我们最近发现了一个新的RAC-CGMP信号通路。小的G蛋白RAC使用其效应子PAK（P21激活激酶）来变构激活跨膜鸟叶烯酸酯酶（GCS）。这些发现揭示了通过CGMP调节生理反应的各种信号受体的一般机制。尽管需要PAK的激酶活性，但PAK并不直接磷酸化GC。取而代之的是，需要PAK的自磷酸化来维持其活化的配置。然后，PAK的活性形式变构激活了跨膜GC。该应用的主要重点是RAC通过其效应子PAK调节跨膜圭尼环酶的活性的生化机制。我们将通过特定目标1中的pak研究跨膜鸟叶尼氏酶的变构激活。在特定目标2中，我们将探索CGMP下游的信号分子。我们将在特定目标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剂。细胞迁移和血管渗透性对于血管发育至关重要，并且参与心血管疾病。 RAC-CGMP途径的信号传导机制和生理功能的研究将显着提高我们对心血管功能和疾病的理解。