Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common cause of renal failure that can be attributed to a genetic mutation at a single locus. Two genes responsible for ADPKD have been identified and cloned. The PKD2 gene encodes polycystin-2, an integral membrane protein that has a molecular eight of 110 kDa and is predicted to span the membrane 6 times. In vitro experiments suggest that polycystin-2 forms homo- oligomers and can interact with polycystin-1, the product of the PKD1 gene. Polycystin-2 exhibits significant structural homology to a family of calcium channels, but nothing is yet known of its function nor of the structural mechanisms through which its mutation causes the dramatic pathology characteristic of ADPKD. The subcellular localization of polycystin-2 has not been established. The molecular signals and cellular mechanisms responsible for targeting polycystin-2 to its site of ultimate functional residence also remain to be determined. The dynamic regulation of the polycystin-2 protein in renal epithelial cells has been investigated, nor is it clear which domains of the protein participate in its proper functioning. We will define the cell biologic properties of polycystin-2 in situ and in heterologous expression systems. Toward this end we will: 1) examine the subcellular distribution of polycystin-2 in its native renal tubular epithelial cells by immunoelectron microscopy and determine the biochemical properties of he compartments in which it accumulates by subcellular fractionation; 2) identify and characterize renal epithelial cell proteins that interact with functionally important domains of the polycystin-2 protein; and 3) elucidate the molecular signals responsible for the sub-cellular distribution of polycystin-2 and identify the mechanisms through which these signals exert their effects. These studies will help to define the range of cellular processes in which polycystin-2 may participate. Investigating the structures with which polycystin-2 associates and elaborating the mechanisms which govern its cell biologic behavior should further our understanding of the pathways through which absent or aberrant polycystin- 2 protein induces disease.
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