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ISRN Molecular Biology
Volume 2012 (2012), Article ID 823875, 9 pages
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.
- 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.
- C. Niehrs, “Function and biological roles of the Dickkopf family of Wnt modulators,” Oncogene, vol. 25, no. 57, pp. 7469–7481, 2006.
- 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.
- 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.
- 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.
- 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.
- 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.
- H. Clevers, “Wnt/β-catenin signaling in development and disease,” Cell, vol. 127, no. 3, pp. 469–480, 2006.
- 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.
- 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.
- 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.
- P. May and J. Herz, “LDL receptor-related proteins in neurodevelopment,” Traffic, vol. 4, no. 5, pp. 291–301, 2003.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.