Pathologic Mechanisms of Polycystic Kidney Disease

常染色体显性遗传性多囊肾病（ADPKD）是由基因突变引起的， 多囊蛋白-1和/或多囊蛋白-2，但导致上皮细胞粘附连接破坏， β-连环蛋白信号通路受损我们的数据显示多囊蛋白在多蛋白复合物中， 粘附连接组件。复合物与质膜微区结合 含有结构脂筏蛋白flotillin-2，但不含有小窝蛋白的类似微区。 粘附连接复合物的破坏与LAR家族受体酪氨酸的下调有关 磷酸酶和复合物中蛋白质的过度磷酸化。由于粘附连接提供了 通过与肌动蛋白细胞骨架的连接， 在ADPKD中受损，这些改变可能有助于疾病病理学。我们 假设flotillin-2膜微区代表多囊蛋白被激活的位点， 与信号分子合作，以实现稳定的细胞-细胞粘附。因此，当多囊蛋白-1 功能突变或缺失时，启动细胞粘附的信号传导发生改变， 潜在的结果。本实验将阐明细胞的组织和功能。 与flotillin-2膜微区相关的含多囊蛋白的多蛋白复合物 探测共定位的酪氨酸激酶和磷酸酶，并通过监测flotilin-2的贡献， 筏对肌动蛋白重构、膜运输和稳定的细胞-细胞粘附的影响。圆满完成 拟议的实验将提供新的，关于事件时间顺序的机械信息， 从多囊蛋白-1激活到E-钙粘蛋白介导的粘附稳定。这些机械的见解 预期可用于设计治疗干预，特别是那些利用激酶 抑制剂的

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the genes encoding polycystin-1 and/or polycystin-2, but results in epithelial cells with disrupted adherensjunctions and compromised beta-catenin signaling pathways. Our data showthe polycystins in a multiprotein complex with adherens junction components. The complexes are associated with plasma membranemicrodomains containing the structural lipid raft protein flotillin-2, but not similar microdomains containing caveolin. Disruption of the adherens junction complexes is linked to down regulation of LAR family receptortyrosine phosphatases and hyperphosphorylation of the proteins in the complex. Since adherens junctions provide structural stability to the epithelial sheet through connections to the actin cytoskeleton, and such connections are compromised in ADPKD, these alterations are likely to contribute to the disease pathology. We hypothesize that flotillin-2 membrane microdomains represent sites wherethe polycystins are activated and cooperate with signaling molecules to bring about stable cell-cell adhesion. Consequently,when polycystin-1 function is mutant or absent, the signaling to initiate cell adhesionis altered and changes in renalcystogenic potential result. The experiments in this proposalwill elucidate the organization and function of the polycystin-containing multiprotein complexes associated with the flotillin-2 membranemicrodomainsby probing for colocalized tyrosine kinases and phosphatases and by monitoringthe contribution of flotillin-2 rafts to actin remodeling, membranetrafficking and stable cell-cell adhesion. Successfulcompletion of the proposed experiments will provide new, mechanistic information on the temporal sequence of eventsleading from polycystin-1activation to the stabilization of E-cadherin mediated adhesion. These mechanistic insights are expected to be useful for designing therapeutic interventions, particularly those that make use of kinase inhibitors.