Patricia D. Wilson
- ADJUNCT PROFESSOR Medicine, Nephrology
B.Sc., University of Nottingham
Ph.D., London University
Imperial Cancer Research Fund
Clinical Research Centre
Elucidation of the normal function of the PKD-encoded polycystins and effects of their mutations in autosomal dominant polycystic kidney disease (ADPKD)
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease inherited as a dominant trait occurring at a rate of 1:800 live births and affectring 500,000 people in US and 4-6 million world wide. 85-90 percent of cases are due to mutations in the PKD1 gene and 10-15 percent are due to mutations in PKD2. Studies in this laboratory are focused on determining the functions of the respective encoded proteins, polycystin-1 and polycystin-2 in their normal and mutant forms associated with renal development and cystic disease. Previous studies have determined that polycystin-1 is developmentally regulated and highly expressed in fetal kidney ureteric bud epithelia with a role in cell adhesion, migration and tubulogenesis. Polycystin-1 forms multiprotein complexes with polycystin-2 and multiple focal adhesion protein components at the basal epithelial cell membrane of fetal cells and with E-cadherin and -catenin at the apical-lateral junctions of adult renal epithelia. In addition, polycystins have been localized to the non-motile central cilia of renal collecting ducts. The intracellular C-terminal domain of polycystin-1 is phosphorylated at several tyrosine and serine sites by focal adhesion kinase (FAK), c-src, protein kinase A(PKA), and protein kinase X (PRKX). In addition a proline -rich SH3 and putative WW site have been identified. The roles of phosphorylation and protein binding motifs in the regulation of normal and mutant intracellular signaling via FAK/MAP kinase/AP-1 or -catenin/TCF pathways is under study. Multiple reporter (EGFP or FLAG) wild-type, truncation and point mutant C-terminal domain PKD1 constructs are used for transfection analysis in conditionally immortalized renal epithelial cell lines derived from human fetal and adult normal proximal, thick ascending limb and collecting tubules as well as cyst lining epithelia from ADPKD and ARPKD kidneys. Assays include polarization of EGFR and NaK-ATPase; matrix adhesion, migration, 3-dimensional tubulogenesis in collagen gels and development in organ culture.
Gross I, Morrison DJ, Hyink DP, Georgas K, English MA, Mericskay M, Hosono S, Sassoon D, Wilson PD, Little M, Licht JD. The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development. J Biol Chem 2003 Oct 17; 278(42): 41420-41430.
Rohatgi R, Greenberg A, Burrow CR, Wilson PD, Satlin LM. Na transport in autosomal recessive polycystic kidney disease (ARPKD) cyst lining epithelial cells. J Am Soc Nephrol 2003 Apr; 14(4): 827-836.
Rogers KK, Wilson PD, Snyder RW, Zhang X, Guo W, Burrow CR, Lipschutz JH. The exocyst localizes to the primary cilium in MDCK cells. Biochem Biophys Res Commun 2004 Jun 18; 319(1): 138-143.
Jouret F, Igarashi T, Gofflot F, Wilson PD, Karet FE, Thakker RV, Devuyst O. Comparative ontogeny, processing, and segmental distribution of the renal chloride channel, ClC-5. Kidney Int 2004 Jan; 65(1): 198-208.
Qiu L, Gans WH, Hyink D, Amsler K, Wilson PD, Burrow CR. Midkine promotes selective expansion of the nephrogenic mesenchyme during kidney organogenesis. organogenesis 2004 Jul; 1(1): 14-21.
Wang S, Luo Y, Wilson PD, Witman GB, Zhou J. The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area. J Am Soc Nephrol 2004 Mar; 15(3): 592-602.
Basson MA, Akbulut S, Watson-Johnson J, Simon R, Carroll TJ, Shakya R, Gross I, Martin GR, Lufkin T, Mcmahon AP, Wilson PD, Costantini FD, Mason IJ, Licht JD. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell 2005 Feb; 8(2): 229-239.
Polgar K, Burrow CR, Hyink DP, Fernandez H, Thornton K, Li X, Gusella GL, Wilson PD. Disruption of polycystin-1 function interferes with branching morphogenesis of the ureteric bud in developing mouse kidneys. Dev Biol 2005 Oct 1; 286(1): 16-30.
Li X, Hyink DP, Polgar K, Gusella GL, Wilson PD, Burrow CR. Protein kinase X activates ureteric bud branching morphogenesis in developing mouse metanephric kidney. J Am Soc Nephrol 2005 Dec; 16(12): 3543-3552.
Ross MJ, Wosnitzer MS, Ross MD, Granelli B, Gusella GL, Husain M, Kaufman L, Vasievich M, D'Agati VD, Wilson PD, Klotman ME, Klotman PE. Role of Ubiquitin-Like Protein FAT10 in Epithelial Apoptosis in Renal Disease. J Am Soc Nephrol 2006 Feb 22; Epub ahead of print.
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