Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease in man inherited as a dominant trait and afflicts 500,000 patients in the US. Many different mutations have been documented in PKD1, the gene responsible for 85% of ADPKD, that encodes a 14.5kb transcript and >460kDa protein, polycystin-1 is a membrane protein with a long extracellular tail with 2 leucine rich repeats and a C-lectin domain, suggesting protein-protein interactions, and a shorter C-terminal domain with a putative tyrosine phosphorylation site of the SH2 group. Our hypothesis is that polycystin-1 is a membrane protein with matrix receptor function that acts to regulate the formation of multi-protein complex and signal transduction pathways by SH2 and SH3 domain mechanisms.
The aims of this proposal are: 1. To determine binding partners for normal polycystin1 (and polycystin2) and the effects of specific mutations on protein-protein interactions. This will be achieved by a combined biochemical, functional and molecular approach using well characterized antibodies and cell lines. 2. To determine the mechanism of matrix-induced intracellular signaling and to identify the intracellular proteins that bind topolycystin-1 and polycystin-2 cytoplasmic SH2 and SH3 binding sites and function in signal transduction. Completion of these studies will lead to an understanding at The molecular level of the function of the normal PLD-1 encoded gene product, polycystin-1, how it interacts with polycystin-2 and, importantly, how specific mutations alter these functions to produce the disease phenotypes.
| Geng, L; Burrow, C R; Li, H P et al. (2000) Modification of the composition of polycystin-1 multiprotein complexes by calcium and tyrosine phosphorylation. Biochim Biophys Acta 1535:21-35 |
| Wilson, P D; Geng, L; Li, X et al. (1999) The PKD1 gene product, ""polycystin-1,"" is a tyrosine-phosphorylated protein that colocalizes with alpha2beta1-integrin in focal clusters in adherent renal epithelia. Lab Invest 79:1311-23 |
