MESANGIAL CELL TYROSINE PHOSPHATASE IN RENAL DISEASE

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We have cloned and partially characterized a novel receptor-like protein tyrosine phosphatase, rPTP-GMC1 ( Kidphos ) that is expressed by mesangial cells that are migrating and proliferating in a rat model of proliferative glomerulonephritis. We have shown that Kidphos has low tyrosine phosphatase activity but can catalyze the dephosphorylation of the 3 position of inositol as well as can PTEN, a PTPase-like protein that has been demonstrated to play an important role in inositol phosphate signaling in vivo. We hypothesize that the 3-phosphatase activity of Kidphos plays a role in regulating the migration and/or proliferation of pericytes and pericyte-like (including mesangial cells and liver stellate cells) during development and in disease processes, and that the activity of Kidphos is determined through regulation of expression level as well as through regulation of catalytic activity/specificity by binding of a ligand/counter-receptor to the extracellular domain. We will test this hypothesis in the following specific aims: Aim 1. Determine the structure, biosynthesis, processing, and subcellular localization of Kidphos protein. Aim 2. Characterize the inositol phosphatase activity of Kidphos and its ability to regulate signaling through phosphatidylinositols. We will test the hypothesis that Kidphos has PIP3 3 phosphatase activity in vivo, and that this activity can regulate signaling downstream of P13Kinase, including proliferation, chemotaxis, and survival. Aim 3. Test the hypothesis that Kidphos is expressed by activated pericyte-like cells during development and in disease processes. Aim 4. Use targeted gene disruption and quantitative chimera analysis to test the hypothesis that Kidphos plays an important role in regulating the migration and/or proliferation of mesangial and pericyte-like cells during development and in disease. Aim 5. Identify the putative ligand/counter-receptor for Kidphos. Based on its deduced structure, we hypothesize that the extracellular domain of Kidphos interacts with a ligand or counter-receptor, and that this interaction regulates the activity or substrate access of the cytoplasmic phosphatase domain. In this aim, we describe the strategy we will use to identify, clone, and use this putative ligand.