FUNCTION OF THE RAS RELATED RAL PROTEINS

这项建议的总体目标是更好地了解 RAS相关Ral蛋白的功能。Rala和RalB出现在 胞质囊泡的膜，包括参与内吞作用的那些 和胞吐作用，尽管相当大比例的蛋白质也是 与质膜相关。作为RAS超级家族的成员 GTP酶、Ral蛋白在活跃的GTP结合和非活跃的GDP之间循环 束缚态。当它们与唯一的结合时在细胞中被激活 核苷酸交换因子，al-Gds和Rg1，并被以下物质灭活 结合到一种独特的GTP酶激活蛋白Ral-GAP。我们最近做了 研究表明，RAS可以通过结合并激活其受体来激活细胞内的RAL 交换系数Ral-Gds。因此，RAL-GDS和RAL的激活代表 新发现的RAS下游信号通路。正在学习Ral 功能可能有助于我们理解RAS蛋白如何影响细胞 分化细胞的增殖、分化和表达 功能。 我们最近还确定了两个与 Ral蛋白的不同区域。其中包括磷脂酶D(PLD)。 这是由RAS信号通路和RAL结合蛋白刺激的 1(RalBP1)，一个新的CDC42和Rac GTP酶的缺口。 这项提案主要关注的是有关al是如何被 RAS和其他可能的上行信号。并对其功能进行了研究。 以及这两个信号分子是如何被 拉尔。最后，本提案中描述的实验将确定 这个新确定的RAS/RAL的重要功能之一是 信号通路是调节细胞分泌和/或内吞作用的途径。

The overall goal of this proposal is to gain a better understanding of the function of Ras-related Ral proteins. RalA and RalB are present in the membranes of cytoplasmic vesicles including those involved in endocytosis and exocytosis, although a significant proportion of the proteins is also associated with the plasma membrane. As members of the Ras superfamily of GTPases, Ral proteins cycle between the active GTP bound and inactive GDP bound states. They are activated in cells upon binding to unique nucleotide exchange factors, Ral-GDS and RGL, and are inactivated by binding to a unique GTPase activating protein, Ral-GAP. We have recently shown that Ras can activate Ral in cells by binding to and activating its exchange factor Ral-GDS. Thus activation of Ral-GDS and Ral represents a newly identified downstream signalling pathway from Ras. Studying Ral function may aid in our understanding of how Ras proteins influence cell proliferation, differentiation and expression of differentiated cell function. We have also recently identified two downstream targets that interact with distinct regions of Ral proteins. These include a phospholipase D (PLD) that is stimulated by the Ras signalling pathway and Ral binding protein 1 (RalBP1), a novel GAP for Cdc42 and Rac GTPases. This proposal focuses on the molecular details of how Ral is regulated by Ras and possibly other upstream signals. It also investigates the function of PLD and RalBP1, and how these two signalling molecules are regulated by Ral. Finally, the experiments described in this proposal will determine whether one of the important functions of this newly identified Ras/Ral signalling pathway is to modulate cellular secretion and/or endocytosis.