Regulation of ADP-ribosylation factor

ADP-核糖基化因子的调节

• 批准号: 7048196
• 负责人: Paul A Randazzo
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7048196
• 关键词: ADP ribosylation; actins; biological signal transduction; cytoskeleton; genetic regulation; guanine nucleotide binding protein; guanosinetriphosphatase activating protein; hydrolysis; intracellular transport; membrane activity; membrane proteins; phosphatidylinositols; phosphorylation; protein localization; protein protein interaction; protein purification; protein structure function; protein tyrosine kinase

Coordinated membrane and actin remodeling are integral to a number of cellular functions, including (i) cell movement, (ii) endocytosis and exocytosis, and (iii) mitosis. A number of signaling molecules that control either or both membrane and actin remodeling include phosphoinositides, Arf family GTP-binding proteins and Rho family GTP-binding proteins. The main objective of the work in our laboratory is to elucidate the mechanisms that regulate signals mediated by Arf family proteins. The work has led to the identification of a family of Arf GTPase-activating proteins, the AZAPs, that may integrate at least four signaling pathways, providing coordinated responses in membranes and actin necessary for complex cellular behaviors. The AZAPs are comprised of four subfamilies: ASAP1/2/3, ACAP1/2/3, AGAP1/2/3 and ARAP1/2/3. Studies with two general goals are being conducted. One emphasis of the laboratory is to examine specific molecular mechanisms by which Arf GAPs interact with Arf and impact Arf activities. In these studies, we will determine (i) the interfaces between Arfs and GAPs; (ii) the interfaces between Arfs and coat proteins; (iii) the catalytic mechanism leading to GTP hydrolysis; (iv) mechanisms regulating GAP activity; and (v) functional interactions among Arfs, GAPs and Arf effectors including coat proteins. Studies to date have led us to propose (i) a new paradigm for the molecular mechanism by which Arf regulates cargo sorting and membrane trafficking, and (ii) an effector function for Arf GAPs of the AZAP family. Ongoing studies include testing these hypotheses and examining Arf GAPs as targets of signaling through tyrosine kinases and phosphoinositides. A second emphasis of the laboratory is an examination of the specific cellular sites of action of AZAP family members. This aim is closely related to the first. Using several strategies we have been determining the site of action for representative Arf GAPs. We have found specific membrane trafficking compartments regulated by some Arf GAPs. For instance, AGAP1 regulates AP-3 endosomes. We have also found that specific cytoskeletal structures are regulated by other Arf GAPs. For instance, ASAP1 regulates focal adhesions. We are currently examining the specific mechanisms that maintain and regulate Arf GAPs at specific sites, and exploring hypotheses about how the membrane trafficking sites may be related to the cytoskeletal sites, including the possibility that the Arf GAPs have GAP-independent functions.

协调的膜和肌动蛋白重塑是许多细胞功能的组成部分，包括(i)细胞运动，（ii）胞吞和胞外作用，以及（iii）有丝分裂。许多控制膜和肌动蛋白重塑的信号分子包括磷酸肌苷、Arf家族gtp结合蛋白和Rho家族gtp结合蛋白。我们实验室工作的主要目的是阐明由Arf家族蛋白介导的信号调节机制。这项工作导致了Arf gtpase激活蛋白家族的鉴定，AZAPs可能整合了至少四种信号通路，在膜和肌动蛋白中提供复杂细胞行为所必需的协调反应。azap由四个亚家族组成：ASAP1/2/3、ACAP1/2/3、AGAP1/2/3和ARAP1/2/3。目前正在进行有两个总体目标的研究。