title: Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common, genetically determined developmental disorder of the kidney that is characterized by cystic expansion of renal tubules and is caused by truncating mutations and haplo-insufficiency of the PKD1 gene. Several defects in cAMP-mediated proliferation and ion secretion have been detected in ADPKD cyst-lining epithelia. Unlike the ubiquitous PKA, the cAMP-dependent CREB-kinase, Protein Kinase X (PRKX) is developmentally regulated, tissue restricted and induces renal epithelial cell migration, and tubulogenesis in vitro as well as branching morphogenesis of ureteric bud in developing kidneys. The possibility of functional interactions between PKD1-encoded polycystin-1 and PRKX was suggested by the renal co-distribution of PRKX and polycystin-1 and the binding and phosphorylation of the C-terminal of polycystin-1 by PRKX at S4166 in vitro. Early consequences of PKD1 mutation include increased tubule epithelial cell-matrix adhesion, decreased migration, reduced ureteric bud branching and aberrant renal tubule dilation. To determine whether PRKX might counteract the adverse effects of PKD1 mutation, human ADPKD epithelial cell lines were transfected with constitutively active PRKX and shown to rescue characteristic adhesion and migration defects. In addition, the co-injection of constitutively active PRKX with inhibitory pMyr-EGFP-PKD1 into the ureteric buds of mouse embryonic kidneys in organ culture resulted in restoration of normal branching morphogenesis without cystic tubular dilations. These results suggest that PRKX can restore normal function to PKD1-deficient kidneys and have implications for the development of preventative therapy for ADPKD.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA. xiaohong.li@mssm.edu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Burrow
authors.forename: Katalin
authors.initials: K
authors.lastname: Polgar
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Hyink
authors.forename: G Luca
authors.initials: GL
authors.lastname: Gusella
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D048430:Cell Shape; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D009924:Organ Culture Techniques; D010766:Phosphorylation; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D050396:TRPP Cation Channels / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D050396:TRPP Cation Channels; C109450:PRKX protein, human