ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner (original) (raw)

References

  1. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006)
    Article CAS Google Scholar
  2. MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009)
    Article CAS Google Scholar
  3. Simons, M. & Mlodzik, M. Planar cell polarity signaling: from fly development to human disease. Annu. Rev. Genet. 42, 517–540 (2008)
    Article CAS Google Scholar
  4. Kazanskaya, O. et al. R-Spondin2 is a secreted activator of Wnt/β-catenin signaling and is required for Xenopus myogenesis. Dev. Cell 7, 525–534 (2004)
    Article CAS Google Scholar
  5. Kim, K. A. et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 309, 1256–1259 (2005)
    Article CAS ADS Google Scholar
  6. Kim, K. A. et al. R-Spondin family members regulate the Wnt pathway by a common mechanism. Mol. Biol. Cell 19, 2588–2596 (2008)
    Article CAS Google Scholar
  7. Ohkawara, B., Glinka, A. & Niehrs, C. Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Dev. Cell 20, 303–314 (2011)
    Article CAS Google Scholar
  8. Aoki, M. et al. R-spondin3 is required for mouse placental development. Dev. Biol. 301, 218–226 (2007)
    Article CAS Google Scholar
  9. Blaydon, D. C. et al. The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nature Genet. 38, 1245–1247 (2006)
    Article CAS Google Scholar
  10. Kazanskaya, O. et al. The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development 135, 3655–3664 (2008)
    Article CAS Google Scholar
  11. Parma, P. et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nature Genet. 38, 1304–1309 (2006)
    Article CAS Google Scholar
  12. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011)
    Article CAS ADS Google Scholar
  13. Ootani, A. et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nature Med. 15, 701–706 (2009)
    Article CAS Google Scholar
  14. Zhao, J. et al. R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathway. Proc. Natl Acad. Sci. USA 106, 2331–2336 (2009)
    Article CAS ADS Google Scholar
  15. Nam, J. S., Turcotte, T. J., Smith, P. F., Choi, S. & Yoon, J. K. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate β-catenin-dependent gene expression. J. Biol. Chem. 281, 13247–13257 (2006)
    Article CAS Google Scholar
  16. Wei, Q. et al. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. J. Biol. Chem. 282, 15903–15911 (2007)
    Article CAS Google Scholar
  17. Binnerts, M. E. et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc. Natl Acad. Sci. USA 104, 14700–14705 (2007)
    Article CAS ADS Google Scholar
  18. Carmon, K. S., Gong, X., Lin, Q., Thomas, A. & Liu, Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proc. Natl Acad. Sci. USA 108, 11452–11457 (2011)
    Article CAS ADS Google Scholar
  19. de Lau, W. et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297 (2011)
    Article CAS ADS Google Scholar
  20. Glinka, A. et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/b-catenin and Wnt/PCP signalling. EMBO Rep. 12, 1055–1061 (2011)
    Article CAS Google Scholar
  21. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chem. Biol. 5, 100–107 (2009)
    Article CAS ADS Google Scholar
  22. Gonzalez-Sancho, J. M., Brennan, K. R., Castelo-Soccio, L. A. & Brown, A. M. Wnt proteins induce dishevelled phosphorylation via an LRP5/6- independent mechanism, irrespective of their ability to stabilize beta-catenin. Mol. Cell. Biol. 24, 4757–4768 (2004)
    Article CAS Google Scholar
  23. Gurney, A. L. Frizzled-binding agents and uses thereof. US patent 201037041. (2011)
  24. Mukai, A. et al. Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt. EMBO J. 29, 2114–2125 (2010)
    Article CAS Google Scholar
  25. Kim, C. H. et al. Repressor activity of Headless/Tcf3 is essential for vertebrate head formation. Nature 407, 913–916 (2000)
    Article CAS ADS Google Scholar
  26. Nasevicius, A. et al. Evidence for a frizzled-mediated wnt pathway required for zebrafish dorsal mesoderm formation. Development 125, 4283–4292 (1998)
    CAS PubMed Google Scholar
  27. Smith, A. N., Miller, L. A., Song, N., Taketo, M. M. & Lang, R. A. The duality of β-catenin function: a requirement in lens morphogenesis and signaling suppression of lens fate in periocular ectoderm. Dev. Biol. 285, 477–489 (2005)
    Article CAS Google Scholar
  28. Kreslova, J. et al. Abnormal lens morphogenesis and ectopic lens formation in the absence of β-catenin function. Genesis 45, 157–168 (2007)
    Article CAS Google Scholar
  29. Machon, O. et al. Lens morphogenesis is dependent on Pax6-mediated inhibition of the canonical Wnt/β-catenin signaling in the lens surface ectoderm. Genesis 48, 86–95 (2010)
    CAS PubMed Google Scholar
  30. Wang, J. et al. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development 133, 1767–1778 (2006)
    Article CAS Google Scholar
  31. Wu, J. et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc. Natl Acad. Sci. USA 108, 21188–21193 (2011)
    Article CAS ADS Google Scholar
  32. Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009)
    Article CAS ADS Google Scholar
  33. Zhang, Y. et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biol. 13, 623–629 (2011)
    Article CAS Google Scholar
  34. Nusslein-Volhard, C. & Dahm, R. Zebrafish. A Practical Approach. (Oxford Univ. Press, 2002)
    Google Scholar
  35. Westerfield, M. _The Zebrafish Book: a Guide for the Laboratory Use of Zebrafish (_Brachydanio rerio). (Univ. Oregon Press, 1995)
    Google Scholar
  36. Goentoro, L. & Kirschner, M. W. Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Mol. Cell 36, 872–884 (2009)
    Article CAS Google Scholar
  37. Gerdes, J. M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nature Genet. 39, 1350–1360 (2007)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank G. Yu, T. Lewis, Q. Song, J. Garver, J. Wang, B. Lu, B. Guo, Q. Fang, X. Shi, J. Sprunger and R.Freeman for technical assistance, R.-F. Kwong and T. Fleming for generating ZNRF3 antibodies, K. Lee and J. Halupowski for mouse maintenance, and J. Tchorz, A. Jaffe, N. Kubica, M. Hild, J. Solomon, Y. Yang, J. Tchorz, E. Wiellette, G. Michaud, D. Cutis and K. Seuwen for comments and advice. We also thank S. Goto for providing FZD4 and FZD4 K0 plasmids.

Author information

Author notes

  1. Yue Zhang
    Present address: Present address: AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.,
  2. Huai-Xiang Hao and Yang Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA
    Huai-Xiang Hao, Yang Xie, Yue Zhang, Olga Charlat, Emma Oster, Monika Avello, Hong Lei, Craig Mickanin, Dong Liu, Xiaohong Mao, Qicheng Ma, Raffaella Zamponi, Peter M. Finan, Jeffery A. Porter, Fabrizio C. Serluca & Feng Cong
  2. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach CH-4002 Basel, Switzerland,
    Heinz Ruffner & Tewis Bouwmeester
  3. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Marc W. Kirschner

Authors

  1. Huai-Xiang Hao
    You can also search for this author inPubMed Google Scholar
  2. Yang Xie
    You can also search for this author inPubMed Google Scholar
  3. Yue Zhang
    You can also search for this author inPubMed Google Scholar
  4. Olga Charlat
    You can also search for this author inPubMed Google Scholar
  5. Emma Oster
    You can also search for this author inPubMed Google Scholar
  6. Monika Avello
    You can also search for this author inPubMed Google Scholar
  7. Hong Lei
    You can also search for this author inPubMed Google Scholar
  8. Craig Mickanin
    You can also search for this author inPubMed Google Scholar
  9. Dong Liu
    You can also search for this author inPubMed Google Scholar
  10. Heinz Ruffner
    You can also search for this author inPubMed Google Scholar
  11. Xiaohong Mao
    You can also search for this author inPubMed Google Scholar
  12. Qicheng Ma
    You can also search for this author inPubMed Google Scholar
  13. Raffaella Zamponi
    You can also search for this author inPubMed Google Scholar
  14. Tewis Bouwmeester
    You can also search for this author inPubMed Google Scholar
  15. Peter M. Finan
    You can also search for this author inPubMed Google Scholar
  16. Marc W. Kirschner
    You can also search for this author inPubMed Google Scholar
  17. Jeffery A. Porter
    You can also search for this author inPubMed Google Scholar
  18. Fabrizio C. Serluca
    You can also search for this author inPubMed Google Scholar
  19. Feng Cong
    You can also search for this author inPubMed Google Scholar

Contributions

H.-X.H. initiated the project, characterized the function of ZNRF3 in cultured cells and mice, and identified ZNRF3 antagonistic antibodies. H.-X.H. and Y.X. discovered the R-spondin and ZNRF3 link. Y.X. led mechanistic studies on R-spondin, LGR4 and ZNRF3. H.-X.H., Y.X., Y.Z., H.L., C.M., D.L., H.R., X.M., Q.M., T.B., P.M.F., M.W.K., J.A.P., F.C.S. and F.C. conceived and designed the study. H.-X.H., Y.X., Y.Z., O.C., E.O., M.A., H.L., C.M., D.L., H.R., X.M., Q.M., R.Z., F.C.S. and F.C. designed and implemented experiments. H.-X.H., Y.X., Y.Z. and F.C. wrote the manuscript.

Corresponding author

Correspondence toFeng Cong.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

PowerPoint slides

Rights and permissions

About this article

Cite this article

Hao, HX., Xie, Y., Zhang, Y. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.Nature 485, 195–200 (2012). https://doi.org/10.1038/nature11019

Download citation