Regulation of ADP-ribosylation factor

ADP-核糖基化因子的调节

• 批准号: 6761994
• 负责人: P 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/6761994
• 关键词: ADP ribosylation; binding proteins; biological signal transduction; genetic regulation; guanine nucleotide binding protein; guanosinetriphosphatase activating protein; phosphorylation; protein purification; protein structure function; protein transport

Coordinated membrane 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 the signals mediated by Arf family proteins. The work has led to the identification of a family of Arf GTPase-activating proteins, the ASAPs, that may integrate at least four signaling pathways, providing coordinated responses in membranes and actin necessary for particular cellular behaviors. The ASAPs are comprised of four subfamilies: ASAP1/2, 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. We have found that the PH domain of one Arf GAP, ASAP1, is an allosteric site regulating catalysis through the Arf GAP domain. In those studies, we also found that ASAP1 contains localization domains that function independently of the PH domain. Using the coat adaptor protein, GGA, as a model, we have also found that interaction of Arf GAP with Arf requires that Arf dissociate from its effector proteins. Based on these data, we have proposed that Arf GAPs bind to the site of Arf action, and senses, through changes in the lipid environment for instance, when Arf should be inactivated. Continuing studies are designed to define the site of interaction between Arf and Arf GAP as well as between Arf and GGA. In addition, we are examining the potential role of Arf GAP - Arf interactions in cargo sorting that occurs during membrane trafficking events such as protein secretion and exocytosis. A second emphasis of the laboratory is an examination of the specific cellular roles of ASAP family members. We have started by examining representative members of each subfamily. ASAP1 has been found to localize to and control the turnover of focal adhesion, structures that anchor cells to the substratum and which must be remodeled for cell movement to occur. ACAP1 has been found to regulate Arf6 dependent actin-rich protrusion formation, an event thought to be involved in cell spreading and movement. ARAP1 has been also found to regulate both membrane trafficking and the actin cytoskeleton, functioning as a node in a signaling network that regulates cell movement. PIP3 binds to ARAP1, activating the Arf GAP, thereby inactivating Arf and controlling Golgi function. In addition, ARAP1 both induces the activation of Cdc42 and the inactivation of Rho. Reciprocal regulation of these two proteins has been found to induce cell migration. Therefore, in general the ASAP family of Arf GAPs appear to regulate events involved in cell migration. Continuing studies are designed to (i) further delineate the role of Arf GAPs in signaling, (ii) identify specific biological events dependent on signaling through Arf GAPs, eg. Development and function of immunological cells and (iii) evaluate a possible involvement in pathological processes, particularly tumor cell invasion and metastasis. Z01 BC 07365-03 LBC to LCO

协调的膜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）胞吞和胞外作用和（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，ASAPs可能整合了至少四种信号通路，在膜和肌动蛋白中提供特定细胞行为所必需的协调反应。ASAPs由四个亚家族组成：ASAP1/2、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。