R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6

  1. Minke E. Binnerts,
  2. Kyung-Ah Kim,
  3. Jessica M. Bright,
  4. Sejal M. Patel,
  5. Karolyn Tran,
  6. Mei Zhou,
  7. John M. Leung,
  8. Yi Liu,
  9. Woodrow E. LomasIII,
  10. Melissa Dixon,
  11. Sophie A. Hazell,
  12. Marie Wagle,
  13. Wen-Sheng Nie,
  14. Nenad Tomasevic,
  15. Jason Williams,
  16. Xiaoming Zhan,
  17. Michael D. Levy,
  18. Walter D. Funk, and
  19. Arie Abo*
  1. Nuvelo, Inc., 201 Industrial Road, Suite 310, San Carlos, CA 94070-6211

  1. Communicated by Lewis T. Williams, Five Prime Therapeutics, Inc., Emeryville, CA, March 13, 2007 (received for review December 1, 2006)

Abstract

The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/β-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.

Footnotes

  • *To whom correspondence should be addressed. E-mail: aabo{at}nuvelo.com

  • Author contributions: M.E.B. and K.-A.K. contributed equally to this work; M.E.B., K.-A.K., and A.A. designed research; J.M.B., S.M.P., K.T., M.Z., J.M.L., Y.L., M.W., W.-S.N., and N.T. performed research; M.D., S.A.H., J.S., N.T., and X.Z. contributed new reagents/analytic tools; M.E.B., K.-A.K., M.D.L., and A.A. analyzed data; and M.E.B., K.-A.K., W.D.F., and A.A. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0702305104/DC1.

  • Abbreviation:
    TCF,
    T cell factor.

  • Freely available online through the PNAS open access option.

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  1. Published online before print September 5, 2007, doi: 10.1073/pnas.0702305104 PNAS September 11, 2007 vol. 104 no. 37 14700-14705
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