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 Brott, B. K.
Right arrow Articles by Sokol, S. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brott, B. K.
Right arrow Articles by Sokol, S. Y.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2002, p. 6100-6110, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6100-6110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Wnt/LRP Signaling by Distinct Domains of Dickkopf Proteins

Barbara K. Brott1,2 and Sergei Y. Sokol1,2*

Department of Microbiology and Molecular Genetics, Harvard Medical School,1 Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 022152

Received 14 January 2002/ Returned for modification 5 March 2002/ Accepted 4 June 2002

Dickkopfs (Dkks) are secreted developmental regulators composed of two cysteine-rich domains. We report that the effects of Dkks depend on molecular context. Although Wnt8 signaling is inhibited by both Dkk1 and Dkk2 in Xenopus embryos, the same pathway is activated upon interaction of Dkk2 with the Wnt coreceptor LRP6. Analysis of individual Dkk domains and chimeric Dkks shows that the carboxy-terminal domains of both Dkks associate with LRP6 and are necessary and sufficient for Wnt8 inhibition, whereas the amino-terminal domain of Dkk1 plays an inhibitory role in Dkk-LRP interactions. Our study illustrates how an inhibitor of a pathway may be converted into an activator and is the first study to suggest a molecular mechanism for how a ligand other than Wnt can positively regulate ß-catenin signaling.


* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Harvard Medical School, and Molecular Medicine Unit, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-3894. Fax: (617) 667-2913. E-mail: ssokol{at}caregroup.harvard.edu.


Molecular and Cellular Biology, September 2002, p. 6100-6110, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6100-6110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Dakhova, O., O'Day, D., Kinet, N., Yucer, N., Wiese, M., Shetty, G., Ducy, P. (2009). Dickkopf-Like1 Regulates Postpubertal Spermatocyte Apoptosis and Testosterone Production. Endocrinology 150: 404-412 [Abstract] [Full Text]  
  • Su, S.-C., Mendoza, E. A., Kwak, H.-i., Bayless, K. J. (2008). Molecular profile of endothelial invasion of three-dimensional collagen matrices: insights into angiogenic sprout induction in wound healing. Am. J. Physiol. Cell Physiol. 295: C1215-C1229 [Abstract] [Full Text]  
  • Wang, K., Zhang, Y., Li, X., Chen, L., Wang, H., Wu, J., Zheng, J., Wu, D. (2008). Characterization of the Kremen-binding Site on Dkk1 and Elucidation of the Role of Kremen in Dkk-mediated Wnt Antagonism. J. Biol. Chem. 283: 23371-23375 [Abstract] [Full Text]  
  • Chen, L., Wang, K., Shao, Y., Huang, J., Li, X., Shan, J., Wu, D., Zheng, J. J. (2008). Structural Insight into the Mechanisms of Wnt Signaling Antagonism by Dkk. J. Biol. Chem. 283: 23364-23370 [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]  
  • Mizobuchi, Y., Matsuzaki, K., Kuwayama, K., Kitazato, K., Mure, H., Kageji, T., Nagahiro, S. (2008). REIC/Dkk-3 induces cell death in human malignant glioma. Neuro Oncol 10: 244-253 [Abstract] [Full Text]  
  • Leamey, C. A., Glendining, K. A., Kreiman, G., Kang, N.-D., Wang, K. H., Fassler, R., Sawatari, A., Tonegawa, S., Sur, M. (2008). Differential Gene Expression between Sensory Neocortical Areas: Potential Roles for Ten_m3 and Bcl6 in Patterning Visual and Somatosensory Pathways. Cereb Cortex 18: 53-66 [Abstract] [Full Text]  
  • Baron, R., Rawadi, G. (2007). Targeting the Wnt/{beta}-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton. Endocrinology 148: 2635-2643 [Abstract] [Full Text]  
  • Guder, C., Pinho, S., Nacak, T. G., Schmidt, H. A., Hobmayer, B., Niehrs, C., Holstein, T. W. (2006). An ancient Wnt-Dickkopf antagonism in Hydra. Development 133: 901-911 [Abstract] [Full Text]  
  • Li, Y., Chen, J., Lu, W., McCormick, L. M., Wang, J., Bu, G. (2005). Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding. J. Cell Sci. 118: 5305-5314 [Abstract] [Full Text]  
  • Wang, Z., Shu, W., Lu, M. M., Morrisey, E. E. (2005). Wnt7b Activates Canonical Signaling in Epithelial and Vascular Smooth Muscle Cells through Interactions with Fzd1, Fzd10, and LRP5. Mol. Cell. Biol. 25: 5022-5030 [Abstract] [Full Text]  
  • Li, X., Zhang, Y., Kang, H., Liu, W., Liu, P., Zhang, J., Harris, S. E., Wu, D. (2005). Sclerostin Binds to LRP5/6 and Antagonizes Canonical Wnt Signaling. J. Biol. Chem. 280: 19883-19887 [Abstract] [Full Text]  
  • Soderhall, I., Kim, Y.-A, Jiravanichpaisal, P., Lee, S.-Y., Soderhall, K. (2005). An Ancient Role for a Prokineticin Domain in Invertebrate Hematopoiesis. J. Immunol. 174: 6153-6160 [Abstract] [Full Text]  
  • Liu, G., Bafico, A., Aaronson, S. A. (2005). The Mechanism of Endogenous Receptor Activation Functionally Distinguishes Prototype Canonical and Noncanonical Wnts. Mol. Cell. Biol. 25: 3475-3482 [Abstract] [Full Text]  
  • Ben-Shlomo, I., Hsueh, A. J. W. (2005). Three's Company: Two or More Unrelated Receptors Pair with the Same Ligand. Mol. Endocrinol. 19: 1097-1109 [Abstract] [Full Text]  
  • Byun, T, Karimi, M, Marsh, J L, Milovanovic, T, Lin, F, Holcombe, R F (2005). Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis. J. Clin. Pathol. 58: 515-519 [Abstract] [Full Text]  
  • Gregory, C. A., Perry, A. S., Reyes, E., Conley, A., Gunn, W. G., Prockop, D. J. (2005). Dkk-1-derived Synthetic Peptides and Lithium Chloride for the Control and Recovery of Adult Stem Cells from Bone Marrow. J. Biol. Chem. 280: 2309-2323 [Abstract] [Full Text]  
  • Wang, X., Adhikari, N., Li, Q., Hall, J. L. (2004). LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 287: H2376-H2383 [Abstract] [Full Text]  
  • Hackam, A. S., Strom, R., Liu, D., Qian, J., Wang, C., Otteson, D., Gunatilaka, T., Farkas, R. H., Chowers, I., Kageyama, M., Leveillard, T., Sahel, J.-A., Campochiaro, P. A., Parmigiani, G., Zack, D. J. (2004). Identification of Gene Expression Changes Associated with the Progression of Retinal Degeneration in the rd1 Mouse. IOVS 45: 2929-2942 [Abstract] [Full Text]  
  • He, X., Semenov, M., Tamai, K., Zeng, X. (2004). LDL receptor-related proteins 5 and 6 in Wnt/{beta}-catenin signaling: Arrows point the way. Development 131: 1663-1677 [Abstract] [Full Text]  
  • Caricasole, A., Ferraro, T., Iacovelli, L., Barletta, E., Caruso, A., Melchiorri, D., Terstappen, G. C., Nicoletti, F. (2003). Functional Characterization of WNT7A Signaling in PC12 Cells: INTERACTION WITH A FZD5{middle dot}LRP6 RECEPTOR COMPLEX AND MODULATION BY DICKKOPF PROTEINS. J. Biol. Chem. 278: 37024-37031 [Abstract] [Full Text]  
  • Itasaki, N., Jones, C. M., Mercurio, S., Rowe, A., Domingos, P. M., Smith, J. C., Krumlauf, R. (2003). Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 130: 4295-4305 [Abstract] [Full Text]  
  • Kawano, Y., Kypta, R. (2003). Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116: 2627-2634 [Abstract] [Full Text]  
  • Kao, L. C., Germeyer, A., Tulac, S., Lobo, S., Yang, J. P., Taylor, R. N., Osteen, K., Lessey, B. A., Giudice, L. C. (2003). Expression Profiling of Endometrium from Women with Endometriosis Reveals Candidate Genes for Disease-Based Implantation Failure and Infertility. Endocrinology 144: 2870-2881 [Abstract] [Full Text]  
  • Boussioutas, A., Li, H., Liu, J., Waring, P., Lade, S., Holloway, A. J., Taupin, D., Gorringe, K., Haviv, I., Desmond, P. V., Bowtell, D. D. L. (2003). Distinctive Patterns of Gene Expression in Premalignant Gastric Mucosa and Gastric Cancer. Cancer Res. 63: 2569-2577 [Abstract] [Full Text]