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ISRN Molecular Biology
Volume 2012 (2012), Article ID 823875, 9 pages
doi:10.5402/2012/823875
Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction
1Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy
2Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy
3High-throughput Screening Unit, Center for Genomic Regulation, Dr. Aiguader, 88, 08003 Barcelona, Spain
Received 13 September 2011; Accepted 4 October 2011
Academic Editors: D. Christophe, A. Maucuer, and A. J. Molenaar
Copyright © 2012 Sara Iozzi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Linked References
- M. V. Semënov, K. Tamai, B. K. Brott, M. Kühl, S. Sokol, and X. He, “Head inducer dickkopf-1 is a ligand for Wnt coreceptor LRP6,” Current Biology, vol. 11, no. 12, pp. 951–961, 2001. View at Publisher · View at Google Scholar · View at Scopus
- C. Niehrs, “Function and biological roles of the Dickkopf family of Wnt modulators,” Oncogene, vol. 25, no. 57, pp. 7469–7481, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- A. Glinka, W. Wu, H. Delius, A. P. Monaghan, C. Blumenstock, and C. Niehrs, “Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction,” Nature, vol. 391, no. 6665, pp. 357–362, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- X. He, M. Semenov, K. Tamai, and X. Zeng, “LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way,” Development, vol. 131, no. 8, pp. 1663–1677, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- K. I. Pinson, J. Brennan, S. Monkley, B. J. Avery, and W. C. Skarnes, “An LDL-receptor-related protein mediates Wnt signalling in mice,” Nature, vol. 407, no. 6803, pp. 535–538, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- K. Tamai, M. Semenov, Y. Kato et al., “LDL-receptor-related proteins in Wnt signal transduction,” Nature, vol. 407, no. 6803, pp. 530–535, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- C. Y. Logan and R. Nusse, “The Wnt signaling pathway in development and disease,” Annual Review of Cell and Developmental Biology, vol. 20, pp. 781–810, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- H. Clevers, “Wnt/β-catenin signaling in development and disease,” Cell, vol. 127, no. 3, pp. 469–480, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- X. Zeng, H. Huang, K. Tamai et al., “Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions,” Development, vol. 135, no. 2, pp. 367–375, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- J. Bilić, Y. L. Huang, G. Davidson et al., “Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation,” Science, vol. 316, no. 5831, pp. 1619–1622, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- D. L. Daniels and W. I. Weis, “β-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation,” Nature Structural and Molecular Biology, vol. 12, no. 4, pp. 364–371, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- P. May and J. Herz, “LDL receptor-related proteins in neurodevelopment,” Traffic, vol. 4, no. 5, pp. 291–301, 2003. View at Scopus
- R. T. Moon, A. D. Kohn, G. V. De Ferrari, and A. Kaykas, “WNT and β-catenin signalling: diseases and therapies,” Nature Reviews Genetics, vol. 5, no. 9, pp. 691–701, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- B. Rubinfeld, I. Albert, E. Porfiri, C. Fiol, S. Munemitsu, and P. Polakis, “Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly,” Science, vol. 272, no. 5264, pp. 1023–1026, 1996. View at Scopus
- M. Van de Wetering, E. Sancho, C. Verweij et al., “The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells,” Cell, vol. 111, no. 2, pp. 241–250, 2002. View at Publisher · View at Google Scholar · View at Scopus
- H. Takeda, S. Lyle, A. J. F. Lazar, C. C. Zouboulis, I. Smyth, and F. M. Watt, “Human sebaceous tumors harbor inactivating mutations in LEF1,” Nature Medicine, vol. 12, no. 4, pp. 395–397, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- C. H. M. Jamieson, L. E. Ailles, S. J. Dylla et al., “Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML,” New England Journal of Medicine, vol. 351, no. 7, pp. 657–667, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- M. Kato, M. S. Patel, R. Levasseur et al., “Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor,” Journal of Cell Biology, vol. 157, no. 2, pp. 303–314, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- M. Semënov, K. Tamai, and X. He, “SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor,” Journal of Biological Chemistry, vol. 280, no. 29, pp. 26770–26775, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- S. I. Harada and G. A. Rodan, “Control of osteoblast function and regulation of bone mass,” Nature, vol. 423, no. 6937, pp. 349–355, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- L. M. Boyden, J. Mao, J. Belsky et al., “High bone density due to a mutation in LDL-receptor-related protein 5,” New England Journal of Medicine, vol. 346, no. 20, pp. 1513–1521, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- B. T. MacDonald, D. M. Joiner, S. M. Oyserman et al., “Bone mass is inversely proportional to Dkk1 levels in mice,” Bone, vol. 41, no. 3, pp. 331–339, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- G. V. De Ferrari and N. C. Inestrosa, “Wnt signaling function in Alzheimer's disease,” Brain Research Reviews, vol. 33, no. 1, pp. 1–12, 2000. View at Publisher · View at Google Scholar · View at Scopus
- J. L. Garrido, J. A. Godoy, A. Alvarez, M. Bronfman, and N. C. Inestrosa, “Protein kinase C inhibits amyloid beta peptide neurotoxicity by acting on members of the Wnt pathway,” The FASEB Journal, vol. 16, no. 14, pp. 1982–1984, 2002. View at Scopus
- N. C. Inestrosa, G. V. De Ferrari, J. L. Garrido et al., “Wnt signaling involvement in β-amyloid-dependent neurodegeneration,” Neurochemistry International, vol. 41, no. 5, pp. 341–344, 2002. View at Publisher · View at Google Scholar
- G. V. De Ferrari, M. A. Chacón, M. I. Barría et al., “Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils,” Molecular Psychiatry, vol. 8, no. 2, pp. 195–208, 2003. View at Publisher · View at Google Scholar · View at PubMed
- A. Caricasole, A. Copani, F. Caraci et al., “Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain,” Journal of Neuroscience, vol. 24, no. 26, pp. 6021–6027, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- C. Scali, F. Caraci, M. Gianfriddo et al., “Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1,” Neurobiology of Disease, vol. 24, no. 2, pp. 254–265, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- I. Cappuccio, A. Calderone, C. L. Busceti et al., “Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death,” Journal of Neuroscience, vol. 25, no. 10, pp. 2647–2657, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- D. Wu, Y. Zhang, P. Liu, et al., “Compositions and methods for bone formation and remodeling,” US Patent application 2005/0196349 A1.
- E. Bettini, E. Magnani, and G. C. Terstappen, “Lithium induces gene expression through lymphoid enhancer-binding factor/T-cell factor responsive element in rat PC12 cells,” Neuroscience Letters, vol. 317, no. 1, pp. 50–52, 2002. View at Publisher · View at Google Scholar · View at Scopus
- K. Willert, J. D. Brown, E. Danenberg et al., “Wnt proteins are lipid-modified and can act as stem cell growth factors,” Nature, vol. 423, no. 6938, pp. 448–452, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- Y. Zhang, Y. Wang, X. Li et al., “The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd,” Molecular and Cellular Biology, vol. 24, no. 11, pp. 4677–4684, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- A. Bafico, G. Liu, A. Yaniv, A. Gazit, and S. A. Aaronson, “Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow,” Nature Cell Biology, vol. 3, no. 7, pp. 683–686, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- J. Mao, J. Wang, B. Liu et al., “Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway,” Molecular Cell, vol. 7, no. 4, pp. 801–809, 2001. View at Publisher · View at Google Scholar · View at Scopus
- M. Kishida, S. Koyama, S. Kishida et al., “Axin prevents Wnt-3a-induced accumulation of β-catenin,” Oncogene, vol. 18, no. 4, pp. 979–985, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- J. Zhao, K. A. Kim, and A. Abo, “Tipping the balance: modulating the Wnt pathway for tissue repair,” Trends in Biotechnology, vol. 27, no. 3, pp. 131–136, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- L. L. Blazer and R. R. Neubig, “Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: Current progress and future hurdles,” Neuropsychopharmacology, vol. 34, no. 1, pp. 126–141, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- H. Glantschnig, K. Scott, R. Hampton et al., “A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody,” Journal of Pharmacology and Experimental Therapeutics, vol. 338, no. 2, pp. 568–569, 2011. View at Publisher · View at Google Scholar · View at PubMed
- H. Glantschnig, R. A. Hampton, P. Lu et al., “Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo,” Journal of Biological Chemistry, vol. 285, no. 51, pp. 40135–40147, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
- A. Caricasole, T. Ferraro, L. Iacovelli et al., “Functional characterization of WNT7A signaling in PC12 cells: interaction with a FZD5-LRP6 receptor complex and modulation by Dickkopf proteins,” Journal of Biological Chemistry, vol. 278, no. 39, pp. 37024–37031, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus