title: Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells.
abstract: Interaction of polycystin-1 (PC1) and Gα12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD). The integrity of cell polarity and cell-cell adhesions (mainly E-cadherin-mediated adherens junction) is altered in the renal epithelial cells of ADPKD. However, the key signaling pathway for this alteration is not fully understood. Madin-Darby canine kidney (MDCK) cells maintain the normal integrity of epithelial cell polarity and adherens junctions. Here, we found that deletion of Pkd1 increased activation of Gα12, which then promoted the cystogenesis of MDCK cells. The morphology of these cells was altered after the activation of Gα12. By using liquid chromatography-mass spectrometry, we found several proteins that could be related this change in the extracellular milieu. E-cadherin was one of the most abundant peptides after active Gα12 was induced. Gα12 activation or Pkd1 deletion increased the shedding of E-cadherin, which was mediated via increased ADAM10 activity. The increased shedding of E-cadherin was blocked by knockdown of ADAM10 or specific ADAM10 inhibitor GI254023X. Pkd1 deletion or Gα12 activation also changed the distribution of E-cadherin in kidney epithelial cells and caused β-catenin to shift from cell membrane to nucleus. Finally, ADAM10 inhibitor, GI254023X, blocked the cystogenesis induced by PC1 knockdown or Gα12 activation in renal epithelial cells. Our results demonstrate that the E-cadherin/β-catenin signaling pathway is regulated by PC1 and Gα12 via ADAM10. Specific inhibition of this pathway, especially ADAM10 activity, could be a novel therapeutic regimen for ADPKD.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Jen X
authors.initials: JX
authors.lastname: Xu
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Tzong-Shi
authors.initials: TS
authors.lastname: Lu
authors.affiliation: Division of Basic Neuroscience, McLean Hospital, Belmont, Massachusetts;
authors.forename: Suyan
authors.initials: S
authors.lastname: Li
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Harvard NeuroDiscovery Center, Boston, Massachusetts; and.
authors.forename: Lai
authors.initials: L
authors.lastname: Ding
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Denker
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; tkong@partners.org.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Kong
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism / Q000473:pathology; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D015820:Cadherins; D004151:Dipeptides; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D006877:Hydroxamic Acids; D050396:TRPP Cation Channels; D051176:beta Catenin; C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide
keywords: ADAM10; ADPKD; E-cadherin; G proteins; polycystin-1