Cell Surface Receptor Trafficking

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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.