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中起重要作用。在某些情况下，活化受体的内化被认为会减弱信号传导过程，而在其他情况下，已提出活化受体在早期内体结构上的聚集对于完全活化信号传导级联至关重要。在任何一种情况下，这些情况表明，细胞表面受体的细胞内运输直接或间接地连接到细胞信号级联。内吞途径和信号级联反应有许多潜在的交叉点。Rab蛋白的激活是信号级联可以影响通过内吞途径的通量的一点，如表达活化形式的Rab 5（GT3缺陷）的细胞表现出通过内吞途径的早期阶段的细胞表面受体的通量增加的事实所证明的。Rab 5的激活由几种鸟嘌呤核苷酸交换因子介导。其中之一，RIN 1本身通过结合Ras.GTP而被激活，并且我们已经提出这种Ras-GTP介导的激活充当信号级联和内吞途径之间的联系。在RIN 1中发现的负责介导Rab 5核苷酸交换的催化结构域是其Vps 9 p结构域。该结构域是高度保守的，并且已经在从芽殖酵母到哺乳动物的大量蛋白质中发现。与RIN 1蛋白家族成员一样，这些蛋白质中的许多除了其Vpsgp结构域之外还含有其他结构域，这为这些蛋白质提供了额外的功能。我们建议，含有Vps 9 p结构域的蛋白质作为特定的Rab 5激活剂，并将各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RIN 1家族的三个成员（RIN 1，RIN 2和RIN 3）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.