Coordination of membrane traffic on the exocytic pathway through rab GEF and rab

通过 rab GEF 和 rab 胞吐途径上的膜运输的协调

• 批准号: 7349784
• 负责人: PETER Jay NOVICK
• 金额: $ 29.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349784
• 关键词: Address; Antigen Presentation; Binding; Binding Proteins; Cell Polarity; Cell Surface Receptors; Cell physiology; Cells; Collection; Complex; Coupled; Diabetes Mellitus; Drosophila genus; Epithelial Cells; GTP Binding; GTPase-Activating Proteins; Glucose Transporter; Golgi Apparatus; Guanine Nucleotide Exchange Factors; Homologous Gene; In Vitro; Insulin; Label; Larva; Link; Lipid Binding; Localized; Maintenance; Malignant Neoplasms; Membrane; Membrane Protein Traffic; Molecular; Molecular Conformation; Nerve Degeneration; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Physiological; Production; Protein Binding; Proteins; Range; Reaction; Recruitment Activity; Regulation; Role; SNAP receptor; Secretory Component; Secretory Vesicles; Sorting - Cell Movement; Staging; Structure; System; Testing; Time; Tumor Suppressor Proteins; Vesicle; human disease; in vivo; neurotransmission; rab GTP-Binding Proteins; response

DESCRIPTION (provided by applicant): Membrane traffic is required for a broad range of essential cellular functions, such as controlling the accessibility of cell surface receptors, the translocation of glucose transporters in response to insulin, antigen presentation, neuronal transmission and the establishment and maintenance of epithelial cell polarity. Therefore, the regulation of membrane traffic is directly relevant to a broad range of human diseases including cancer, diabetes and neural degeneration. Rab GTPases are key regulators of membrane traffic. By recruiting and activating a functionally diverse set of effectors, a single Rab GTPase can coordinate the various sub- reactions within a given stage of membrane traffic, including vesicle budding, delivery, tethering and fusion. Furthermore, our results indicate that adjacent stages of transport can also be coupled through coordinated rab regulation. We recently defined a rab guanine nucleotide exchange factor (GEF) cascade in which one rab, in its GTP-bound state, recruits the GEF that activates the next rab along the exocytic pathway. We also have preliminary evidence for a rab GTPase activating protein (GAP) cascade operating in a counter current fashion. Here the downstream rab recruits the GAP that inactivates the upstream rab. The net effect is rab conversion in which a given patch of membrane starts out labeled with one rab, but over time becomes labeled with another rab. Since each rab recruits and activates a distinct set of effectors, this leads to a functional maturation of the membrane. We will explore these two cascade mechanisms in further detail and test the physiological consequences of uncoupling adjacent stages of membrane traffic. We will test the role of a Sec4p effector in SNARE assembly and explore the roles of several new putative Sec4p effectors. Through these studies we will begin to define the exocytic pathway as a fully coordinated system, rather than as a collection of isolated sub-reactions. Membrane traffic is the mechanism by which material is transferred between different compartments within the cell and the regulation of membrane traffic is directly relevant to a broad range of human diseases including cancer, diabetes and neural degeneration. This study addresses the molecular mechanisms by which different stages of membrane traffic are coordinately regulated.

描述（由申请人提供）：多种必需细胞功能需要膜流量，例如控制细胞表面受体的可及性，葡萄糖转运蛋白的易位，响应胰岛素，抗原表现，神经元传播以及上皮细胞极性的建立和维持。因此，膜流量的调节与包括癌症，糖尿病和神经变性在内的广泛人类疾病直接相关。 RAB GTPases是膜流量的关键调节剂。通过募集和激活功能多样化的效应子，单个RAB GTPase可以在给定的膜流量的给定阶段（包括囊泡萌芽，递送，绑扎和融合）协调各种子反应。此外，我们的结果表明，相邻的运输阶段也可以通过协调的RAB调节耦合。我们最近定义了一个Rab鸟嘌呤核苷酸交换因子（GEF）级联，其中一个RAB在其GTP结合状态下，招募了GEF，该GEF沿沿外旋转途径激活下一个RAB。我们也有初步证据表明，Rab GTPase激活蛋白（GAP）以反电流方式运行的级联反应。在这里，下游Rab招募了使上游Rab失活的差距。网络效果是RAB转换，其中给定的一块膜开始用一个Rab标记，但随着时间的流逝，另一个Rab被标记。由于每个RAB都募集并激活一组不同的效应子，因此这会导致膜的功能成熟。我们将进一步详细探讨这两种级联机制，并测试膜交通相邻阶段的生理后果。我们将测试SEC4P效应子在军鼓组装中的作用，并探索几个新推定的SEC4P效应子的作用。通过这些研究，我们将开始将外囊肿途径定义为完全协调的系统，而不是孤立的子反应集合。膜流量是在细胞内不同隔室之间转移材料的机制，并且膜流量的调节与包括癌症，糖尿病和神经变性在内的广泛的人类疾病直接相关。这项研究探讨了分子机制，通过协调膜流量的不同阶段。