The polycystin 1-C-terminal fragment stimulates ERK-dependent spreading of renal epithelial cells.
Polycystin 1, the product of the PKD1 gene, is mutated in autosomal dominant polycystic kidney disease, a disease characterized by renal cyst formation and progressive renal failure. We show that expression of the C-terminal domain of human polycystin-1 (PKD1-CT) triggers spreading of isolated inner medullary collecting duct cells, a process mediated by Erk. As inner medullary collecting duct cells spread, PKD1-CT localizes to cell-extracellular matrix contacts, interacts with focal adhesion proteins Fak and paxillin, and stimulates Fak phosphorylation, paxillin phosphorylation, Fak-paxillin association, and formation of small focal complexes. PKD1-CT-mediated spreading requires membrane localization and the integrity of the C-terminal protein binding sites. We additionally show that Pkd1 null proximal tubule cells generated from Pkd1(flox/-):TSLargeT mice by in vitro Cre recombinase transfection demonstrate diminished spreading when compared with Pkd(flox/-) heterozygous parental cells. These findings suggest that membrane-bound PC1 has a central role in regulating morphogenic protein signaling at cell-matrix interfaces in non-confluent cells.
Joly
Dominique
D
Université Paris-Descartes, Faculté deMédecine, INSERM U813, Hôpital Necker-Enfants-Malades 75743 Paris Cedex 15, France. joly@necker.fr
Ishibe
Shuta
S
Nickel
Christian
C
Yu
Zhiheng
Z
Somlo
Stefan
S
Cantley
Lloyd G
LG
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051419:Paxillin / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels / Q000378:metabolism*
D048049:Extracellular Signal-Regulated MAP Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051419:Paxillin; D010446:Peptide Fragments; D017452:Receptors, IgG; D050396:TRPP Cation Channels