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MESANGIAL CELL TYROSINE PHOSPHATASE IN RENAL DISEASE

肾病中的系膜细胞酪氨酸磷酸酶

基本信息

批准号：
6523756
负责人：
DANIEL F BOWEN-POPE
金额：
$ 26.56万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-15 至 2004-07-31
项目状态：
已结题

项目摘要

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.

我们克隆并部分表征了一种新型受体样蛋白酪氨酸磷酸酶 rPTP-GMC1 (Kidphos)，该酶由增殖性肾小球肾炎大鼠模型中迁移和增殖的系膜细胞表达。我们已经证明，Kidphos 具有较低的酪氨酸磷酸酶活性，但可以催化肌醇 3 位的去磷酸化，并且可以催化 PTEN（一种 PTPase 样蛋白，已被证明在体内肌醇磷酸信号传导中发挥重要作用）。我们假设Kidphos的3-磷酸酶活性在发育和疾病过程中调节周细胞和周细胞样（包括系膜细胞和肝星状细胞）的迁移和/或增殖中发挥作用，并且Kidphos的活性是通过调节表达水平以及通过配体/反受体与配体/反受体结合来调节催化活性/特异性来确定的。胞外域。我们将在以下具体目标中检验这一假设：目标 1. 确定 Kidphos 蛋白的结构、生物合成、加工和亚细胞定位。目标 2. 表征 Kidphos 的肌醇磷酸酶活性及其通过磷脂酰肌醇调节信号传导的能力。我们将测试 Kidphos 在体内具有 PIP3 3 磷酸酶活性的假设，并且该活性可以调节 P13 激酶下游的信号传导，包括增殖、趋化性和存活。目标 3. 检验 Kidphos 在发育和疾病过程中由活化的周细胞样细胞表达的假设。目标 4. 使用靶向基因破坏和定量嵌合体分析来检验这样的假设：Kidphos 在调节发育和疾病期间系膜和周细胞样细胞的迁移和/或增殖中发挥重要作用。目标 5. 确定 Kidphos 的假定配体/反受体。根据其推导的结构，我们假设 Kidphos 的胞外结构域与配体或反受体相互作用，并且这种相互作用调节细胞质磷酸酶结构域的活性或底物进入。为此，我们描述了用于识别、克隆和使用这种假定配体的策略。