Regulation of ADP-ribosylation factor

ADP-核糖基化因子的调节

• 批准号: 7965101
• 负责人: Paul A Randazzo
• 金额: $ 130.51万
• 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/7965101
• 关键词: ADP-Ribosylation Factors; Actins; Affect; Behavior; Capsid Proteins; Cell physiology; Clathrin; Clathrin Adaptors; Complex; Cytoskeleton; Data; Dorsal; Endocytosis; Endosomes; Epidermal Growth Factor Receptor; Exocytosis; Family; Family member; Focal Adhesions; GTP-Binding Proteins; GTPase-Activating Proteins; Glioblastoma; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Hydrolysis; Kinetics; Laboratories; Link; Malignant Neoplasms; Mediating; Membrane; Membrane Protein Traffic; Mitosis; Modeling; Molecular; Neoplasm Metastasis; Pathologic; Pathologic Processes; Pathology; Phosphatidylinositols; Phosphorylation; Protein Family; Protein Tyrosine Kinase; Reading; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sorting - Cell Movement; Structure; System; Testing; Time; Transport Vesicles; Tumor Cell Invasion; Work; Yang; analog; base; carcinogenesis; cell motility; design; protein B; protein function; receptor; response; rho; rho GTP-Binding Proteins; trafficking

Coordinated membrane and actin remodeling are integral to a number of cellular functions, including (i) cell movement, (ii) endocytosis and exocytosis, and (iii) mitosis and are central to pathological processes such as tumor cell invasion and metastasis. 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: ASAP, ACAP, AGAP and ARAP. Three AZAP family members have been directly implicated in carcinogenesis. Studies with two general goals are being conducted. <BR><BR>One emphasis of the laboratory is to examine specific molecular mechanisms by which Arf GAPs interact with Arf and regulate Arf function. 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. <BR><BR>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 and ARAP1 regulates EGFR endocytic traffic. We have also found that specific cytoskeletal structures are regulated by other Arf GAPs. For instance, ASAP1 regulates focal adhesions, circular dorsal ruffles and invadopodia. 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. The most recent hypotheses that we are currently testing are (i) that Arf GAPs are in the Rho family signaling pathway with some Arf GAPs functioning as Rho effectors and (ii) Arf GAPs are targets of Src that are of crucial importance for the formation of podosomes and their pathologic analogs invadopia. <BR><BR><BR><BR>Z01 BC 07365-03 LBC to LCO

协调的膜和肌动蛋白重塑是许多细胞功能所必需的，包括(I)细胞运动，(Ii)内吞和胞吐，以及(Iii)有丝分裂，并且是肿瘤细胞侵袭和转移等病理过程的中心。许多控制膜和肌动蛋白重塑的信号分子包括磷脂酰肌醇、Arf家族GTP结合蛋白和Rho家族GTP结合蛋白。本实验室工作的主要目的是阐明Arf家族蛋白调节信号的机制。这项工作导致了一个Arf GTPase激活蛋白家族的鉴定，AZAPs可能整合了至少四条信号通路，在膜和肌动蛋白中提供复杂细胞行为所需的协调反应。AZAP由ASAP、ACAP、AGAP和ARAP四个亚家族组成。AZAP家族的三名成员直接参与了癌症的发生。目前正在进行有两个总体目标的研究。该实验室的重点之一是研究Arf间隙与Arf相互作用并调节Arf功能的特定分子机制。在这些研究中，我们将确定(1)ARF和GAP之间的界面；(2)ARF和外壳蛋白之间的界面；(3)导致GTP水解的催化机制；(4)调节GAP活性的机制；以及(5)ARF、GAP和包括外壳蛋白在内的ArF效应器之间的功能相互作用。到目前为止的研究已经引导我们提出了(I)Arf调节货物分拣和膜运输的分子机制的新范式，以及(Ii)AZAP家族Arf间隙的效应函数。正在进行的研究包括验证这些假说，并检查Arf间隙作为酪氨酸激酶和磷酸肌醇信号转导的靶标。实验室的第二个重点是研究AZAP家族成员的特定细胞作用部位。这一目标与第一个目标密切相关。使用几种策略，我们一直在确定有代表性的ARF差距的行动地点。我们已经发现了受一些Arf间隙调控的特定的膜转运间隔。例如，AGAP1调节AP-3内含体，ARAP1调节EGFR内吞运输。我们还发现，特定的细胞骨架结构受其他Arf间隙的调节。例如，ASAP1调控局灶性粘连、圆形背部褶皱和内翻足。我们目前正在研究维持和调节特定部位的Arf间隙的具体机制，并探索膜转运部位可能与细胞骨架部位相关的假说。我们目前正在检验的最新假设是：(I)Arf间隙存在于Rho家族的信号通路中，其中一些Arf间隙作为Rho效应器发挥作用；(Ii)Arf间隙是Src的靶标，对足体的形成及其病理类似物invadia至关重要。&lt；BR&>；&lt；BR&>；Z01 BC 07365-03 LBC至LCO