This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liu, G.
Right arrow Articles by Aaronson, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liu, G.
Right arrow Articles by Aaronson, S. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2005, p. 3475-3482, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3475-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Mechanism of Endogenous Receptor Activation Functionally Distinguishes Prototype Canonical and Noncanonical Wnts

Guizhong Liu, Anna Bafico, and Stuart A. Aaronson*

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York

Received 15 October 2004/ Returned for modification 10 November 2004/ Accepted 1 February 2005

Wnt glycoproteins are developmentally essential signaling molecules, and lesions afflicting Wnt pathways play important roles in human diseases. Some Wnts signal to the canonical pathway by stabilizing ß-catenin, while others lack this activity. Frizzled serpentine receptors mediate distinct signaling pathways by both classes of Wnts. Here, we tandemly linked noncanonical Wnt5a with the C-terminal half of Dickkopf-2 (Dkk2C), a distinct ligand of the Wnt coreceptor LRP5/6. Whereas Wnt5a, Dkk2C, or both together were incapable of stimulating endogenous canonical signaling, the Wnt5a/Dkk2C chimera efficiently activated this pathway in a manner inhibitable by specific antagonists of either frizzled or LRP receptors. Thus, activation of the canonical pathway requires ligand coupling of an endogenous frizzled/LRP coreceptor complex, rather than Wnt triggering each receptor independently. Moreover, fusion of Wnt5a with Dkk2C unmasked its ability to signal to Dishevelled through multiple frizzleds, indicating that the lack of functional interaction with LRP distinguishes noncanonical Wnt5a from canonical Wnts in mammalian cells. These findings provide a novel mechanism by which the same receptor can be switched between distinct signaling pathways depending on the differential recruitment of a coreceptor by members of the same ligand family.

* Corresponding author. Mailing address: Department of Oncological Sciences, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 659-5400. Fax: (212) 987-2240. E-mail: stuart.aaronson{at}mssm.edu.

Molecular and Cellular Biology, May 2005, p. 3475-3482, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3475-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • van Amerongen, R., Nusse, R. (2009). Towards an integrated view of Wnt signaling in development. Development 136: 3205-3214 [Abstract] [Full Text]  
  • Liu, G., Vijayakumar, S., Grumolato, L., Arroyave, R., Qiao, H., Akiri, G., Aaronson, S. A. (2009). Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells. JCB 185: 67-75 [Abstract] [Full Text]  
  • van Amerongen, R., Mikels, A., Nusse, R. (2008). Alternative Wnt Signaling Is Initiated by Distinct Receptors. Sci Signal 1: re9-re9 [Abstract] [Full Text]  
  • Liu, X., Engelhardt, J. F. (2008). The Glandular Stem/Progenitor Cell Niche in Airway Development and Repair. Proc Am Thorac Soc 5: 682-688 [Abstract] [Full Text]  
  • Semenov, M. V., Zhang, X., He, X. (2008). DKK1 Antagonizes Wnt Signaling without Promotion of LRP6 Internalization and Degradation. J. Biol. Chem. 283: 21427-21432 [Abstract] [Full Text]  
  • Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., Almeida, K., Wang, J., Doble, B., Woodgett, J., Wynshaw-Boris, A., Hsieh, J.-C., He, X. (2008). Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135: 367-375 [Abstract] [Full Text]  
  • Khan, Z., Vijayakumar, S., de la Torre, T. V., Rotolo, S., Bafico, A. (2007). Analysis of Endogenous LRP6 Function Reveals a Novel Feedback Mechanism by Which Wnt Negatively Regulates Its Receptor. Mol. Cell. Biol. 27: 7291-7301 [Abstract] [Full Text]  
  • Hitchins, M. P., Lin, V. A., Buckle, A., Cheong, K., Halani, N., Ku, S., Kwok, C.-T., Packham, D., Suter, C. M., Meagher, A., Stirzaker, C., Clark, S., Hawkins, N. J., Ward, R. L. (2007). Epigenetic Inactivation of a Cluster of Genes Flanking MLH1 in Microsatellite-Unstable Colorectal Cancer. Cancer Res. 67: 9107-9116 [Abstract] [Full Text]  
  • Bryja, V., Schulte, G., Rawal, N., Grahn, A., Arenas, E. (2007). Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism. J. Cell Sci. 120: 586-595 [Abstract] [Full Text]  
  • Semenov, M. V., He, X. (2006). LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST. J. Biol. Chem. 281: 38276-38284 [Abstract] [Full Text]  
  • Lindvall, C., Evans, N. C., Zylstra, C. R., Li, Y., Alexander, C. M., Williams, B. O. (2006). The Wnt Signaling Receptor Lrp5 Is Required for Mammary Ductal Stem Cell Activity and Wnt1-induced Tumorigenesis. J. Biol. Chem. 281: 35081-35087 [Abstract] [Full Text]  
  • Blumenthal, A., Ehlers, S., Lauber, J., Buer, J., Lange, C., Goldmann, T., Heine, H., Brandt, E., Reiling, N. (2006). The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood 108: 965-973 [Abstract] [Full Text]  
  • Yin, Y.-J., Katz, V., Salah, Z., Maoz, M., Cohen, I., Uziely, B., Turm, H., Grisaru-Granovsky, S., Suzuki, H., Bar-Shavit, R. (2006). Mammary Gland Tissue Targeted Overexpression of Human Protease-Activated Receptor 1 Reveals a Novel Link to {beta}-Catenin Stabilization.. Cancer Res. 66: 5224-5233 [Abstract] [Full Text]  
  • Cadigan, K. M., Liu, Y. I. (2006). Wnt signaling: complexity at the surface. J. Cell Sci. 119: 395-402 [Abstract] [Full Text]  
  • Povelones, M., Howes, R., Fish, M., Nusse, R. (2005). Genetic Evidence That Drosophila frizzled Controls Planar Cell Polarity and Armadillo Signaling by a Common Mechanism. Genetics 171: 1643-1654 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»