Regulation der Signalantwort in Podozyten durch CD2AP/CIN85

CD 2AP和CIN 85是可以调节不同细胞信号级联的衔接分子。在足细胞中，这两种分子具有特殊的作用，因为它们影响狭缝隔膜的稳定性和Nephrin的表面表达。在该提案的过去阶段，我们能够证明CD 2AP和CIN 85都与nephrin结合，具有完全不同的结果。CD 2AP/Nephrin结合具有稳定作用，而CIN 85/Nephrin结合对于狭缝隔膜具有更不稳定的作用。 我们可以证明，CD 2AP对CIN 85的SUMO化有直接影响，并通过这种机制影响游离结合活性CIN 85的表达。我们可以表明，CD 2AP是酪氨酸磷酸化依赖于细胞因子的刺激，这种酪氨酸磷酸化影响的CD 2AP和Nephrin的结合亲和力。 本研究的目的是阐明CD 2AP和CIN 85的酪氨酸磷酸化如何影响信号传导、CD 2AP/CIN 85蛋白平衡和裂膜蛋白nephrin的周转。这项工作的结果将有助于理解蛋白尿发展的病理生理学，并可能导致肾小球疾病的新诊断标志物和新治疗方法的发展。

CD2AP and CIN85 are adaptor-molecules that can regulate different cellular signaling-cascades. In podocytes these two molecules have a special role since they influence the stability of the slit diaphragm and the surface expression of Nephrin. In the past phase of this proposal we were able to demonstrate that CD2AP and CIN85 both bind to nephrin with totally different consequences. The CD2AP/Nephrin-binding has a stabilizing role, while the CIN85/Nephrin-binding has a more destabilizing role for the slit diaphragm. We could demonstrate that CD2AP has a direct influence on SUMOylation of CIN85 and influences via this mechanism the expression of free binding-active CIN85. We could show that CD2AP is tyrosine phosphorylated depending on cytokine stimulations and that this tyrosine phosphorylation influences the binding affinity of CD2AP and Nephrin. The aim of this proposal is to clarify how tyrosine-phosphorylation of CD2AP and CIN85 influences signaling, CD2AP/CIN85 protein balance and turnover of the slit diaphragm protein nephrin. Results from this work will contribute to the understanding of the pathophysiology of proteinuria development and can lead to the development of novel diagnostic markers and novel therapeutical startegies in glomerular diseases.