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      Jade-1 inhibits Wnt signaling by ubiquitinating β-catenin and mediates Wnt pathway inhibition by pVHL

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          Abstract

          The von Hippel-Lindau protein pVHL suppresses renal tumorigenesis in part by promoting degradation of hypoxia-inducible HIF-alpha transcription factors 1, and additional mechanisms have been proposed 2. pVHL also stabilizes plant homeodomain (PHD) protein Jade-1, which is a candidate renal tumor suppressor that may correlate with renal cancer risk 3- 5. We show here that Jade-1 binds the oncoprotein β-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type β-catenin, but not a cancer-causing form of β-catenin. While β-TrCP ubiquitinates only phosphorylated β-catenin 6, Jade-1 ubiquitinates both phosphorylated and non-phosphorylated β-catenin and therefore regulates canonical Wnt signaling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of β-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL down-regulates β-catenin in a Jade-1-dependent manner and inhibits Wnt signaling, supporting a role for Jade-1 and Wnt signaling in renal tumorigenesis. The pVHL tumor suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.

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          Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

          Eek-hoon Jho, Tong Zhang, Claire Domon … (2002)
          Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2 . Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.
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            Wnt signaling in disease and in development.

            Roel Nusse (2005)
            The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.
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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.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 8 December 2009
                Publication date (Electronic): 21 September 2008
                Publication date (Print): October 2008
                Publication date PMC-release: 2 March 2010
                Volume: 10
                Issue: 10
                Pages: 1208-1216
                Affiliations
                [1 ]Renal Section, Department of Medicine, Boston University School of Medicine, Boston
                [2 ]Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Boston
                [3 ]Molecular Stress Response Unit, Department of Medicine, Boston University School of Medicine, Boston
                [4 ]Hematology-Oncology Section, Department of Medicine, Boston University School of Medicine, Boston
                [5 ]Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
                Author notes
                Corresponding author: Herbert T. Cohen, MD, Renal and Hematology-Oncology Sections, Boston University School of Medicine, 650 Albany Street, EBRC X-535, Boston, MA 02118. (O) (617) 638-7322. (F) (617) 638-7326 htcohen@ 123456bu.edu
                Article
                Manuscript ID: nihpa69979
                DOI: 10.1038/ncb1781
                PMC ID: 2830866
                PubMed ID: 18806787
                SO-VID: bf8cee19-2b41-4fa0-be94-a41827ba1338
                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Cancer Institute : NCI
                Award ID: T32 DK007053-32 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Cancer Institute : NCI
                Award ID: R01 DK067569-05 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA079830-08 ||CA
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA071796-11 ||CA
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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