Regulation der Signalantwort in Podozyten durch CD2AP/CIN85

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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.