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      A polycystin-centric view of cyst formation and disease: the polycystins revisited

      research-article
      Author(s): 1 , 2
      Publication date (Electronic):
      Journal: Kidney international
      Keywords: ADPKD, PKD1, PKD2, polycystin-1, polycystin-2, TRPP2, primary cilia, cysts

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          Abstract

          It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs have led in turn to a period of intense investigation into the function of the two proteins encoded, polycystin-1 and polycystin-2 and how defects in either protein lead to cyst formation and non-renal phenotypes. In this review, we summarise the major findings in this area and present a current model of how the polycystin proteins function in health and disease.

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          YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

          Luca Azzolin, Tito Panciera, Sandra Soligo … (2014)
          The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 469 times – based on 0 reviews     Review now
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            The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

            Jonathan Shillingford, Noel Murcia, Claire H. Larson … (2006)
            Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.
            Article 0 comments Cited 211 times – based on 0 reviews     Review now
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              Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways.

              Matias Simons, Joachim Gloy, Athina Ganner … (2005)
              Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.
              Article 0 comments Cited 162 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0323470
                Journal ID (pubmed-jr-id): 5428
                Journal ID (nlm-ta): Kidney Int
                Journal ID (iso-abbrev): Kidney Int.
                Title: Kidney international
                ISSN (Print): 0085-2538
                ISSN (Electronic): 1523-1755
                Publication date Nihms-submitted: 16 June 2015
                Publication date (Electronic): 22 July 2015
                Publication date (Print): October 2015
                Publication date PMC-release: 01 April 2016
                Volume: 88
                Issue: 4
                Pages: 699-710
                Affiliations
                [1 ]Kidney Genetics Group, Academic Nephrology Unit, Department of Infection and Immunity, University of Sheffield Medical School, Sheffield, UK
                [2 ]Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
                Author notes
                Correspondence: Albert CM Ong ( a.ong@ 123456sheffield.ac.uk ) or Peter C. Harris ( harris.peter@ 123456mayo.edu )
                Article
                Manuscript ID: EMS63858
                DOI: 10.1038/ki.2015.207
                PMC ID: 4589452
                PubMed ID: 26200945
                SO-VID: ba76e80e-0475-4054-8284-d31e0e35780c
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Subject: Article

                ScienceOpen disciplines: Nephrology
                Keywords: adpkd,pkd1,pkd2,polycystin-1,polycystin-2,trpp2,primary cilia,cysts
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: adpkd, pkd1, pkd2, polycystin-1, polycystin-2, trpp2, primary cilia, cysts

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