Cell Surface Receptor Trafficking

描述(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着重要作用。在某些情况下，激活的受体的内化被认为减弱了信号传递过程，而在另一些情况下，激活的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关键。在任何一种情况下，这些情景都表明细胞表面受体的细胞内运输直接或间接地与细胞信号级联有关。有许多潜在的点，内吞途径和信号级联可以相交。Rab蛋白的激活是信号级联影响通过内吞途径的通量的一个点，表达激活形式的Rab5(GTPase缺陷)的细胞通过内吞途径的早期阶段表现出细胞表面受体通量的增加。Rab5的激活是由几种鸟核苷酸交换因子介导的。其中，RIN1本身被结合Ras.GTP激活，我们认为这种Ras-GTP介导的激活是信号级联和内吞途径之间的纽带。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。这个结构域高度保守，在从萌芽酵母到哺乳动物的大量蛋白质中都有发现。与RIN1蛋白家族成员一样，这些蛋白中的许多除了Vpsgp结构域之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。我们认为，包含Vps9p结构域的蛋白质作为特异性Rab5激活剂，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RIN1家族的三个成员(RIN1、RIN2和RIN3)在受体介导的内吞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.