Cell Surface Receptor Trafficking

描述（由申请人提供）：细胞表面受体的内吞作用在调节细胞信号级联反应中起重要作用。在某些情况下，被激活受体的内化被认为会减弱信号传导过程，而在其他情况下，被激活受体在早期内体结构上的聚集被认为是完全激活信号级联的必要条件。在这两种情况下，这些情况都表明细胞内的细胞表面受体运输与细胞信号级联直接或间接相关。在许多潜在的点上，内吞途径和信号级联可以相交。Rab5蛋白的激活是信号级联反应影响内吞途径通量的一个点，表达活化形式的Rab5 （GTPase缺陷）的细胞在内吞途径的早期阶段表现出细胞表面受体通量增加的事实证明了这一点。Rab5的活化是由几种鸟嘌呤核苷酸交换因子介导的。其中之一，RIN1本身通过结合Ras激活。我们提出Ras-GTP介导的激活是信号级联反应和内吞途径之间的联系。在RIN1中发现的负责介导Rab5核苷酸交换的催化结构域是它的vps9p结构域。这个结构域是高度保守的，在从芽殖酵母到哺乳动物的大量蛋白质中都发现了这个结构域。像RIN1蛋白家族成员一样，许多这些蛋白除了它们的Vpsgp结构域外还含有其他结构域，这些结构域为这些蛋白提供了额外的功能。我们提出含有Vps9p结构域的蛋白质作为特定的Rab5激活因子，并将多种细胞过程的调节与内吞途径联系起来。为了验证这一假设，我们将确定RIN1家族的三个成员（RIN1， RIN2和RIN3）在受体介导的内吞作用过程中的确切功能作用。

DESCRIPTION (provided by applicant): Endocytosis of cell surface receptors plays an important role in regulating cell signaling cascades. In some cases, internalization of an activated receptor is thought to attenuate the signaling process, while in other cases the clustering of activated receptors on early endosomal structures have been proposed to be essential for fully activating signaling cascades. In either case, these scenarios indicate that the intracellular trafficking of cell surface receptors are linked directly or indirectly to cell signaling cascades. There are many potential points at which the endocytic pathway and signaling cascades can intersect. The activation of Rab proteins is one point that signaling cascades could influence flux through the endocytic pathway as demonstrated by the fact that cells expressing activated forms of Rab5 (GTPase defective) exhibit increased flux of cell surface receptors through the early stages of the endocytic pathway. The activation of Rab5 is mediated by several guanine nucleotide exchange factors. One of these, RIN1 is itself activated by binding Ras.GTP and we have proposed that this Ras-GTP mediated activation serves as a link between signaling cascades and the endocytic pathway. The catalytic domain found in RIN1 that is responsible for mediating Rab5 nucleotide exchange is its Vps9p-domain. This domain is highly conserved and has been found in a large number of proteins from budding yeast to mammals. Like the RIN1 protein family members, many of these proteins contain other domains in addition to their Vpsgp domain, which offer additional functionalities to these proteins. We propose that proteins that contain the Vps9p domain serve as specific Rab5 activators and link the regulation of a variety of cellular processes to the endocytic pathway. To test this hypothesis we will determine the precise functional role of the three members of the RIN1 family (RIN1, RIN2 and RIN3) in the process of receptor mediated endocytosis.