Regulation of ADP-ribosylation factor

协调的膜和肌动蛋白重塑是许多细胞的组成部分， 功能，包括（i）细胞运动，（ii）内吞作用和胞吐作用，以及（iii）有丝分裂和 是病理过程如肿瘤细胞侵袭和转移的核心。一些 控制膜和肌动蛋白重塑之一或两者的信号分子包括 磷酸肌醇，Arf家族GTP结合蛋白和Rho家族GTP结合蛋白。的 我们实验室工作的主要目标是阐明调节 由Arf家族蛋白介导的信号。这项工作导致了一个家庭的确定， Arf GTP酶激活蛋白，AZAP，可以整合至少四种信号传导， 途径，提供协调的反应，在膜和肌动蛋白所必需的复杂 细胞行为AZAP由四个亚家族组成：ASAP 1/2/3，ACAP 1/2/3， AGAP 1/2/3和ARAP 1/2/3。三名AZAP家族成员直接参与了 致癌作用目前正在进行有两个总目标的研究。 实验室的一个重点是检查特定的 Arf GAP与Arf相互作用并调节Arf功能的分子机制。在这些 研究，我们将确定（一）Arfs和GAP之间的接口;（二）接口 之间的Arfs和外壳蛋白;（iii）催化机制导致GTP水解;（iv） 调节GAP活性的机制;以及（v）Arf、GAP和Arf之间的功能相互作用 包括外壳蛋白的效应物。迄今为止的研究使我们提出了（i）一个新的范式 Arf调节货物分选和膜运输的分子机制， (ii)AZAP家族的Arf GAP的效应子功能。正在进行的研究包括测试 这些假设和检查Arf GAP作为通过酪氨酸激酶的信号传导的靶点， 磷酸肌醇。实验室的第二个重点是 检查AZAP家族成员作用的特定细胞位点。该目的是 与第一个密切相关。使用几种策略，我们一直在确定网站的 代表性Arf GAP的行动。我们发现了特定的膜运输区室 由一些Arf GAP监管。例如，AGAP 1调节AP-3内体。我们还发现 特定的细胞骨架结构受到其他Arf GAP的调控。例如，ASAP 1 调节局部粘连。我们目前正在研究维持 并在特定位点调节Arf GAP，并探索关于膜如何 运输位点可能与细胞骨架位点有关。最新的假设是， 目前正在测试的是（i）Arf GAP在Rho家族信号通路中， Arf GAP作为Rho效应子发挥作用，（ii）Arf GAP是Src的靶点， 重要性的形成podosomes和他们的病理类似invadopia。 Z 01 BC 07365 -03 LBC至 LCO

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: ASAP1/2/3, ACAP1/2/3, AGAP1/2/3 and ARAP1/2/3. Three AZAP family members have been directly implicated in carcinogenesis. 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 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. 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. 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. Z01 BC07365-03 LBC to LCO