The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells.
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.
Nickel
Christian
C
Section of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut 06529-8029, USA.
Benzing
Thomas
T
Sellin
Lorenz
L
Gerke
Peter
P
Karihaloo
Anil
A
Liu
Zhen-Xiang
ZX
Cantley
Lloyd G
LG
Walz
Gerd
G
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
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