Pathologic Mechanisms of Polycystic Kidney Disease

University Of New Mexico, Albuquerque NM

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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 adherens junctions and compromised beta-catenin signaling pathways. Our data show the polycystins in a multiprotein complex with adherens junction components. The complexes are associated with plasma membrane microdomains 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 receptor tyrosine 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 where the 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 adhesion is altered and changes in renal cystogenic potential result. The experiments in this proposal will elucidate the organization and function of the polycystin-containing multiprotein complexes associated with the flotillin-2 membrane microdomains by probing for colocalized tyrosine kinases and phosphatases and by monitoring the contribution of flotillin-2 rafts to actin remodeling, membrane trafficking and stable cell-cell adhesion. Successful completion of the proposed experiments will provide new, mechanistic information on the temporal sequence of events leading from polycystin-1 activation 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. [unreadable] [unreadable] [unreadable]