ADPKD is one of the most common autosomal genetic disorders, affecting approximately 1/1000 individuals. It is characterized by progressive renal cyst development, typically leading to end stage renal disease in late middle age. ADPKD is caused by mutations in the PKD1 or PKD2 genes, which encode the polycystin-1 (PC1) and polycystin-2 (PC2) proteins, respectively. PC1 is a membrane protein that may be involved in signaling from sites of cell-cell contact, while PC2 is a transmembrane protein that shares homology with calcium channels. These two proteins appear to participate in the same signaling pathway; however, their functions are largely unknown. A new signaling paradigm known as regulated intramembrane proteolysis (RIP) has been recently described. In this model, the cytoplasmic portion of a transmembrane receptor is released after ligand interaction and enters the nucleus, where it directly acts as a modulator of gene expression. During the previous funding period of this award we have found that PC1 undergoes a RIP-like proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli. PC2 modulates the signaling properties of the PC1 CTT, and appears to serve as a cytoplasmic buffer that modulates the quantity of CTT available to enter the nucleus. In order to explore further the role that this cleavage plays in the normal functioning of the polycystin proteins and in the pathogenesis of ADPKD we will 1) identify the enzyme responsible for the release of the PC1 CTT; 2) identify the stimuli and signaling pathways that induce or prevent the cleavage and 3) identify the protein partners with which the CTT fragment interacts and define the collection of genes whose expression is altered through nuclear translocation of the CTT fragment. These studies will begin to unravel the relationship between the cleavage of the PC1 CTT and the pathogenesis of ADPKD, and may perhaps suggest new targets for therapeutic intervention.