title: The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells.
abstract: Mutations of either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease, a syndrome characterized by extensive formation of renal cysts and progressive renal failure. Homozygous deletion of Pkd1 or Pkd2, the genes encoding polycystin-1 and polycystin-2, disrupt normal renal tubular differentiation in mice but do not affect the early steps of renal development. Here, we show that expression of the C-terminal 112 amino acids of human polycystin-1 triggers branching morphogenesis and migration of inner medullary collecting duct (IMCD) cells, and support in vitro tubule formation. The integrity of the polycystin-2-binding region is necessary but not sufficient to induce branching of IMCD cells. The C-terminal domain of polycystin-1 stimulated protein kinase C-alpha (PKC-alpha), but not the extracellular signal-regulated kinases ERK1 or ERK2. Accordingly, inhibition of PKC, but not ERK, prevented polycystin-1-mediated IMCD cell morphogenesis. In contrast, HGF-mediated morphogenesis required ERK activation but was not dependent on PKC. Our findings demonstrate that the C-terminal domain of polycystin-1, acting in a ligand-independent fashion, triggers unique signaling pathways for morphogenesis, and likely plays a central role in polycystin-1 function.
authors.affiliation: Section of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut 06529-8029, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Nickel
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Lorenz
authors.initials: L
authors.lastname: Sellin
authors.forename: Peter
authors.initials: P
authors.lastname: Gerke
authors.forename: Anil
authors.initials: A
authors.lastname: Karihaloo
authors.forename: Zhen-Xiang
authors.initials: ZX
authors.lastname: Liu
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D004847:Epithelial Cells / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D007684:Kidney Tubules / Q000166:cytology* / Q000254:growth & development*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics* / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051571:Protein Kinase C-alpha; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D050396:TRPP Cation Channels
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D010446:Peptide Fragments; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D011506:Proteins; D050396:TRPP Cation Channels; C496628:PRKCA protein, human; C496630:Prkca protein, mouse