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

描述（由申请方提供）：膜运输是广泛的基本细胞功能所必需的，例如控制细胞表面受体的可及性、葡萄糖转运蛋白响应胰岛素的易位、抗原呈递、神经元传递以及上皮细胞极性的建立和维持。因此，膜运输的调节与包括癌症、糖尿病和神经变性在内的广泛的人类疾病直接相关。Rab GTP酶是膜运输的关键调节剂。通过募集和激活一组功能多样的效应物，单个Rab GTdR可以协调膜运输的给定阶段内的各种子反应，包括囊泡出芽、递送、拴系和融合。此外，我们的研究结果表明，相邻阶段的运输也可以耦合通过协调rab调节。我们最近定义了一个rab鸟嘌呤核苷酸交换因子（GEF）级联反应，其中一个rab在其GTP结合状态下招募GEF，该GEF激活下一个rab沿着胞吐途径。我们也有初步的证据，rab GT3激活蛋白（GAP）级联反应以逆流的方式运作。在这里，下游的rab招募差距，使上游的rab失活。净效应是rab转换，其中给定的膜片开始标记有一个rab，但随着时间的推移，会标记有另一个rab。由于每个rab招募并激活一组不同的效应器，这导致膜的功能成熟。我们将进一步详细探讨这两个级联机制，并测试分离膜交通相邻阶段的生理后果。我们将测试一个Sec4p效应器在陷阱组装中的作用，并探索几个新的假定Sec4p效应器的作用。通过这些研究，我们将开始将胞吐途径定义为一个完全协调的系统，而不是孤立的子反应的集合。膜运输是物质在细胞内不同区室之间转移的机制，膜运输的调节与广泛的人类疾病直接相关，包括癌症，糖尿病和神经变性。本研究探讨了不同阶段的膜交通协调调节的分子机制。

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.