Can we safely target the WNT pathway?

Nature Reviews Drug Discovery

Volumn 13, Issue 7, 2014, Pages 513-532

  Kahn, Michael ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APC PROTEIN; AXIN; BETA CATENIN; BETA CATENIN CREB BINDING PROTEIN ANTAGONIST; BETA CATENIN T CELL FACTOR ANTAGONIST; BIOLOGICAL PRODUCT; BLOCKING AGENT; CASEIN KINASE IALPHA; CGP 049090; DISHEVELLED PROTEIN; ENZYME INHIBITOR; FJ 9; GLYCOGEN SYNTHASE KINASE 3BETA; LGK 974; LITHIUM; NONSTEROID ANTIINFLAMMATORY AGENT; NOTCH RECEPTOR; NSC 668036; OMP 54F28; PKF 115 584; PNU 74654; POLYPHENOL; PORCUPINE INHIBITOR; PRI 724; PYRVINIUM EMBONATE; RETINOL; TANKYRASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANTICTUMAB; VITAMIN D; 7,8 DIHYDRO 2 [4 (TRIFLUOROMETHYL)PHENYL] 5H THIOPYRANO[4,3 D]PYRIMIDIN 4 OL; ANTINEOPLASTIC AGENT; CELECOXIB; CWP 232291; CYCLIC AMP DEPENDENT PROTEIN KINASE; DICKKOPF 1 PROTEIN; FORKHEAD TRANSCRIPTION FACTOR; IMATINIB; LITHIUM SALT; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 6; MOLECULAR THERAPY AGENT; PROSTAGLANDIN; QUERCETIN; RING FINGER PROTEIN; SCATTER FACTOR; SCLEROSTIN; STRESS ACTIVATED PROTEIN KINASE; SULINDAC; UVOMORULIN; VISMODEGIB; WNT PROTEIN;

AGING; ALZHEIMER DISEASE; AUTOIMMUNE DISEASE; CELLULAR, SUBCELLULAR AND MOLECULAR BIOLOGICAL PHENOMENA AND FUNCTIONS; CLINICAL DECISION MAKING; CLINICAL TRIAL (TOPIC); COLITIS; DISEASE ASSOCIATION; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; ENDOCRINE DISEASE; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIAL REPAIR; FIBROSIS; HEART INFARCTION; HUMAN; LOSS OF FUNCTION MUTATION; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; MOLECULARLY TARGETED THERAPY; NEOPLASM; NEURAL TUBE DEFECT; NEUROLOGIC DISEASE; NONHUMAN; OSTEOPOROSIS; PATHOPHYSIOLOGY; PDZ DOMAIN; PRIORITY JOURNAL; PROTEIN FUNCTION; REGENERATIVE MEDICINE; REVIEW; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION; TERATOGENICITY; WILLIAMS BEUREN SYNDROME; WNT SIGNALING PATHWAY; ABDOMINAL PAIN; ACUTE GRANULOCYTIC LEUKEMIA; ALOPECIA; BASAL CELL CARCINOMA; BIPOLAR DISORDER; BODY WEIGHT DISORDER; CANCER STEM CELL; COLON CANCER; COLORECTAL CANCER; CONSTIPATION; DIARRHEA; DOWN REGULATION; DRUG DETERMINATION; DRUG DOSE ESCALATION; DRUG PROTEIN BINDING; DYSGEUSIA; ENZYME ACTIVATION; EPIGENETICS; FATIGUE; FRACTURE; GENE MUTATION; GENE TRANSLOCATION; HYPERBILIRUBINEMIA; MALIGNANT NEOPLASTIC DISEASE; MUSCLE CRAMP; MUSCLE SPASM; NAUSEA; PROTEIN EXPRESSION; PROTEIN INTERACTION; SOLID TUMOR; VOMITING;

ADULT; ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS; WNT PROTEINS; WNT SIGNALING PATHWAY;

EID: 84903767326     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4233     Document Type: Review

References (294)

1. Nusse, R. & Varmus, H. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99-109 (1982
2. Baker, N. E. Molecular cloning of sequences from wingless, a segment polarity gene in Drosophila: The spatial distribution of a transcript in embryos. EMBO J. 6, 1765-1773 (1987
3. McMahon, A. P. & Moon, R. T. Ectopic expression of the proto-oncogene int 1 in Xenopus embryos leads to duplication of the embryonic axis. Cell 58, 1075-1084 (1989
4. Logan, C. Y. & Nusse, R. The Wnt signaling pathway in Development and disease. Annu. Rev. Cell Dev. Biol. 20, 781-810 (2004
5. van Amerongen, R. & Nusse, R. Towards an integrated view of Wnt signaling in Development. Development 136, 3205-3214 (2009
6. Alonso, L. & Fuchs, E. Stem cells in the skin: Waste not, Wnt not. Genes Dev. 17, 1189-1200 (2003
7. Pinto, D. & Clevers, H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp. Cell Res. 306, 357-363 (2005
8. Nemeth, M. J., Mak, K. K., Yang, Y. & Bodine, D. M. β-catenin expression in the bone marrow microenvironment is required for long-Term maintenance of primitive hematopoietic cells. Stem Cells 27, 1109-1119 (2009
9. Malhotra, S. & Kincade, P. W. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell 4, 27-36 (2009
10. Monga, S. P. Role of Wnt/β catenin signaling in liver metabolism and cancer. Int. J. Biochem. Cell Biol. 43, 1021-1029 (2011
11. Beers, M. F. & Morrisey, E. E. The three R's of lung health and disease: Repair, remodeling, and regeneration. J. Clin. Invest. 121, 2065-2073 (2011
12. Whyte, J. L., Smith, A. A. & Helms, J. A. Wnt signaling and injury repair. Cold Spring Harb. Perspect. Biol. 4, a008078 (2012
13. Inestrosa, N. C. & Arenas, E. Emerging roles of Wnts in the adult nervous system. Nature Rev. Neurosci. 11, 77-86 (2010
14. Cisternas, P., Henriquez, J. P., Brandan, E. & Inestrosa, N. C. Wnt signaling in skeletal muscle dynamics: Myogenesis, neuromuscular synapse and fibrosis. Mol. Neurobiol. 49, 574-589 (2013
15. Webster, M. R. & Weeraratna, A. T. A. Wnt er migration: The confusing role of β catenin in melanoma metastasis. Sci. Signal. 6, e11 (2013
16. Hoffmeyer, K. et al. Wnt/β catenin signaling regulates telomerase in stem cells and cancer cells. Science 336, 1549-1554 (2012
17. Rawson, J. B. et al. Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br. J. Cancer 104, 1906-1912 (2011
18. Alberici, P. & Fodde, R. The role of the APC tumor suppressor in chromosomal instability. Genome Dyn. 1, 149-170 (2006
19. Frisch, S. M., Schaller, M. & Cieply, B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J. Cell Sci. 126, 21-29 (2013
20. Pecinas-Slaus, N. Wnt signal transduction pathway and apoptosis: A review. Cancer Cell. Int. 10, 22 (2010
21. Porfiri, E. et al. Induction of a β-catenin-LEF 1 complex by wnt 1 and transforming mutants of β-catenin. Oncogene 15, 2833-2839 (1997
22. de La Coste, A. et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847-8851 (1998
23. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nature Rev. Cancer 13, 11-26 (2013
24. Dees, C. & Distler, J. H. Canonical Wnt signaling as a key-regulator of fibrogenesis - implications for targeted therapies?. Exp. Dermatol. 22, 710-713 (2013
25. Chilosi, M. et al. Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol. 162, 1495-1502 (2003
26. Schinner, S. Wnt-signalling and the metabolic syndrome. Horm. Metab. Res. 41, 159-163 (2009
27. Inestrosa, N. C., Montecinos-Oliva, C. & Fuenzalida, M. Wnt signaling: Role in Alzheimer disease and schizophrenia. J. Neuroimmune Pharmacol. 7, 788-807 (2012
28. Berwick, D. C. & Harvey, K. The importance of Wnt signalling for neurodegeneration in Parkinson's disease. Biochem. Soc. Trans. 40, 1123-1128 (2012
29. Okerlund, N. D. & Cheyette, B. N. Synaptic Wnt signaling - A contributor to major psychiatric disorders?. J. Neurodev. Disord. 3, 162-174 (2011
30. Niehrs, C. The complex world of WNT receptor signalling. Nature Rev. Mol. Cell. Biol. 13, 767-779 (2012
31. Veeman, M. T., Axelrod, J. & Moon, R. T. A second canon. Functions and mechanisms of β-catenin-independent Wnt signaling. Dev. Cell 5, 367-377 (2003
32. Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nature Rev. Mol. Cell. Biol. 10, 468-477 (2009
33. Nusse, R. & Varmus, H. Three decades of Wnts: A personal perspective on how a scientific field developed. EMBO J. 31, 2670-2684 (2012
34. Fagotto, F. Looking beyond the Wnt pathway for the deep nature of β catenin. EMBO Rep. 14, 422-433 (2013
35. Miller, R. K., Hong, J. Y., Muρoz, W. A. & McCrea, P. D. β-catenin versus the other armadillo catenins: Assessing our current view of canonical Wnt signaling. Prog. Mol. Biol. Transl. Sci. 116, 387-407 (2013
36. Brembeck, F. H., Rosrio, M. & Birchmeier, W. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr. Opin. Genet. Dev. 16, 51-59 (2006
37. van Veelen, W. et al. β catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis. Gut 60, 1204-1212 (2011
38. Kawabata, A. Prostaglandin E2 and pain - An update. Biol. Pharm. Bull. 34, 1170-1173 (2011
39. Gumbiner, B. M. Carcinogenesis: A balance between β-catenin and APC. Curr. Biol. 7, R444-R446 (1997
40. Rubinfeld, B. et al. Binding of GSK3β to the APC-β- catenin complex and regulation of complex assembly. Science 272, 1023-1026 (1996
41. Brunner, E., Peter, O., Schweizer, L. & Basler, K. Pangolin encodes a Lef 1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila. Nature 385, 829-833 (1997
42. van De Wetering, M. et al. Armadillo coactivates transcription Driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789-799 (1997
43. Takemaru, K. I. & Moon, R. T. The transcriptional coactivator CBP interacts with β-catenin to activate gene expression. J. Cell Biol. 149, 249-254 (2000
44. Hecht, A., Vleminckx, K., Stemmler, M. P., van Roy, F. & Kemler, R. The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates. EMBO J. 19, 1839-1850 (2000
45. Rasola, A. et al. A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth. Oncogene 26, 1078-1087 (2007
46. Coluccia, A. M. et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 26, 1456-1466 (2007
47. Kim, Y. M. et al. The γ catenin/CBP complex maintains survivin transcription in β catenin Deficient/depleted cancer cells. Curr. Cancer Drug Targets 11, 213-225 (2011
48. Maeda, O. et al. Plakoglobin (γ-catenin) has TCF/LEF family-dependent transcriptional activity in β-catenin-deficient cell line. Oncogene 23, 964-972 (2004
49. Jeannet, G. et al. Long-Term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142-149 (2008
50. Le, N. H., Franken, P. & Fodde, R. Tumour-stroma interactions in colorectal cancer: Converging on β-catenin activation and cancer stemness. Br. J. Cancer 98, 1886-1893 (2008
51. Polakis, P. Drugging Wnt signalling in cancer. EMBO J. 31, 2737-2746 (2012); erratum 31, 3375 (2012
52. Zimmerman, Z. F., Moon, R. T. & Chien, A. J. Targeting Wnt pathways in Disease. Cold Spring Harb. Perspect. Biol. 4, a008086 (2012
53. Herr, P., Hausmann, G. & Basler, K. WNT secretion and signalling in human Disease. Trends Mol. Med. 18, 483-493 (2012
54. Clevers, H. & Nusse, R. Wnt/β catenin signaling and disease. Cell 149, 1192-1205 (2012
55. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589-600 (1991
56. Kinzler, K. W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661-665 (1991
57. Bodmer, W. F. Cancer genetics: Colorectal cancer as a model. J. Hum. Genet. 51, 391-396 (2006
58. Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45-51 (2007
59. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643-649 (1998
60. Clements, W. M., Lowy, A. M. & Groden, J. Adenomatous polyposis coli/β-catenin interaction and downstream targets: Altered gene expression in gastrointestinal tumors. Clin. Colorectal Cancer 3, 113-120 (2003
61. Drier, Y. et al. Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability. Genome Res. 23, 228-235 (2013
62. Rubinfeld, B. et al. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275, 1790-1792 (1997
63. Han, Z. G. Functional genomic studies: Insights into the pathogenesis of liver cancer. Annu. Rev. Genom. Hum. Genet. 13, 171-205 (2012
64. Sastre-Perona, A. & Santisteban, P. Role of the wnt pathway in thyroid cancer. Front. Endocrinol. 3, 31 (2012
65. Gatcliffe, T. A., Monk, B. J., Planutis, K. & Holcombe, R. F. Wnt signaling in ovarian tumorigenesis. Int. J. Gynecol. Cancer 18, 954-962 (2008
66. Caldwell, G. M. et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res. 64, 883-888 (2004
67. Lee, A. Y. et al. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene 23, 6672-6676 (2004
68. Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36, 417-422 (2004
69. Fukui, T. et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24, 6323-6327 (2005
70. Zou, H. et al. Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus. Int. J. Cancer 116, 584-591 (2005
71. Rhee, C. et al. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 21, 6598-6605 (2002
72. Wong, S. C. et al. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J. Pathol. 196, 145-153 (2002
73. Milovanovic, T. et al. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 25, 1337-1342 (2004
74. Okino, K. et al. Up regulation and overproduction of DVL 1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma. Oncol. Rep. 10, 1219-1223 (2003
75. Uematsu, K. et al. Wnt pathway activation in mesothelioma: Evidence of Dishevelled overexpression and transcriptional activity of β-catenin. Cancer Res. 63, 4547-4551 (2003
76. Uematsu, K. et al. Activation of the Wnt pathway in non small cell lung cancer: Evidence of dishevelled overexpression. Oncogene 22, 7218-7221 (2003
77. Kikuchi, A. & Yamamoto, H. Tumor formation Due to abnormalities in the β-catenin-independent pathway of Wnt signaling. Cancer Sci. 99, 202-208 (2008
78. Cao, X., Eu, K. W., Seow-Choen, F., Zao, Y. & Cheah, P. Y. APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients. Eur. J. Hum. Genet. 8, 42-48 (2000
79. Takada, T. et al. Methylation-Associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers. Cancer Sci. 95, 741-744 (2004
80. Lugli, A. et al. Prognostic significance of the wnt signalling pathway molecules APC, β-catenin and E cadherin in colorectal cancer: A tissue microarray-based analysis. Histopathology 50, 453-464 (2007
81. Kageshita, T. et al. Loss of β-catenin expression associated with disease progression in malignant melanoma. Br. J. Dermatol. 145, 210-216 (2001
82. Maelandsmo, G. M., Holm, R., Nesland, J. M., Fodstad, . & Flrenes, V. A. Reduced β-catenin expression in the cytoplasm of advanced-stage superficial spreading malignant melanoma. Clin. Cancer Res. 9, 3383-3388 (2003
83. Bachmann, I. M., Straume, O., Puntervoll, H. E., Kalvenes, M. B. & Akslen, L. A. Importance of P cadherin, β-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin. Cancer Res. 11, 8606-8614 (2005
84. Chien, A. J. et al. Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc. Natl Acad. Sci. USA 106, 1193-1198 (2009
85. Bakker, E. R. et al. β catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene 32, 4579-4585 (2013
86. Salinas, P. C. & Zou, Y. Wnt signaling in neural circuit assembly. Annu. Rev. Neurosci. 31, 339-354 (2008
87. Freese, J. L., Pino, D. & Pleasure, S. J. Wnt signaling in Development and disease. Neurobiol. Dis. 38, 148-153 (2010
88. Millar, J. K., Christie, S., Semple, C. A. & Porteous, D. J. Chromosomal location and genomic structure of the human translin-Associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics 67, 69-77 (2000
89. Blackwood, D. H. et al. Schizophrenia and affective disorders - cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family. Am. J. Hum. Genet. 69, 428-433 (2001
90. Mao, Y. et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3β/β-catenin signaling. Cell 136, 1017-1031 (2009
91. Courchesne, E. et al. Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study. Neurology 57, 245-254 (2001
92. Courchesne, E., Carper, R. & Akshoomoff, N. Evidence of brain overgrowth in the first year of life in autism. J. Am. Med. Assoc. 290, 337-344 (2003
93. Sparks, B. F. et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 59, 184-192 (2002
94. Schumann, C. M. et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J. Neurosci. 24, 6392-6401 (2004
95. Chenn, A. & Walsh, C. A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365-369 (2002
96. Chenn, A. & Walsh, C. A. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in β-catenin overexpressing transgenic mice. Cereb. Cortex 13, 599-606 (2003
97. Kalkman, H. O. A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. Mol. Autism 3, 10 (2012
98. Kang, D. E. et al. Presenilin couples the paired phosphorylation of β-catenin independent of axin: Implications for β-catenin activation in tumorigenesis. Cell 110, 751-762 (2002
99. De Ferrari, G. V. et al. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc. Natl Acad. Sci. USA 104, 9434-9439 (2007
100. Wang, R., Dineley, K. T., Sweatt, J. D. & Zheng, H. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126, 305-312 (2004
101. Teo, J. L., Ma, H., Nguyen, C., Lam, C. & Kahn, M. Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin 1 mutation. Proc. Natl Acad. Sci. USA 102, 12171-12176 (2005
102. Crews, L., Patrick, C., Adame, A., Rockenstein, E. & Masliah, E. Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease. Cell Death Dis. 2, e120 (2011
103. Liebner, S. & Plate, K. H. Differentiation of the brain vasculature: The answer came blowing by the Wnt. J. Angiogenes. Res. 2, 1 (2010
104. Dickins, E. M. & Salinas, P. C. Wnts in action: From synapse formation to synaptic maintenance. Front. Cell Neurosci. 7, 162 (2013
105. Li, B. et al. WNT5A signaling contributes to Aβ induced neuroinflammation and neurotoxicity. PLoS ONE 6, e22920 (2011
106. Hackam, A. S. The Wnt signaling pathway in retinal degenerations. IUBMB Life 57, 381-388 (2005
107. Lepiscopo, F. et al. A Wnt1 regulated Frizzled 1/ β catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-Astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection. Mol. Neurodegener. 6, 49 (2011
108. Hamblet, N. S. et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129, 5827-5838 (2002
109. Zeng, L. et al. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90, 181-192 (1997
110. Carter, M. et al. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Proc. Natl Acad. Sci. USA 102, 12843-12848 (2005
111. Kokubu, C. et al. Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131, 5469-5480 (2004
112. Pinson, K. I., Brennan, J., Monkley, S., Avery, B. J. & Skarnes, W. C. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535-538 (2000
113. Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A. & Korenberg, J. R. Bridging cognition, the brain and molecular genetics: Evidence from Williams syndrome. Trends Neurosci. 22, 197-207 (1999
114. Doyle, T. F., Bellugi, U., Korenberg, J. R. & Graham, J. "Everybody in the world is my friend" hypersociability in young children with Williams syndrome. Am. J. Med. Genet. A 124A, 263-273 (2004
115. Zhao, C. et al. Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval. Development 132, 2917-2927 (2005
116. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513-523 (2001
117. Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513-1521 (2002
118. Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation During vertebrate skeletogenesis. Dev. Cell 8, 739-750 (2005
119. Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231-3244 (2006
120. Glass, D. A. et al. Canonical Wnt signaling in Differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751-764 (2005
121. Holmen, S. L. et al. Essential role of β-catenin in postnatal bone acquisition. J. Biol. Chem. 280, 21162-21168 (2005
122. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883-19887 (2005
123. Semnov, M., Tamai, K. & He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280, 26770-26775 (2005
124. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578-588 (2009
125. Little, R. D., Recker, R. R. & Johnson, M. L. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 347, 943-944 (2002
126. Ellies, D. L. et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738-1749 (2006
127. Semnov, M. & He, X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276-38284 (2006
128. Hoeppner, L. H., Secreto, F. J. & Westendorf, J. J. Wnt signaling as a therapeutic target for bone diseases. Expert Opin. Ther. Targets 13, 485-496 (2009
129. Zaidan, M. et al. Increased risk of solid renal tumors in lithium-Treated patients. Kidney Int. http://dx.doi.org/10.1038/ki.2014.2 (2014
130. Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989-2003 (2009
131. Surendran, K., Schiavi, S. & Hruska, K. A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis J. Am. Soc. Nephrol. 16, 2373-2384 (2005
132. Myung, S. J. et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS Lett. 581, 2954-2958 (2007
133. Knigshoff, M. et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 3, e2142 (2008
134. Henderson, W. R. Jr. et al. Inhibition of Wnt/β-catenin/ CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc. Natl Acad. Sci. USA 107, 14309-14314 (2010
135. Hao, S. et al. Targeted inhibition of β catenin/CBP signaling ameliorates renal interstitial fibrosis. J. Am. Soc. Nephrol. 22, 1642-1653 (2011
136. Konigshoff, M. et al. WNT1 inducible signaling protein 1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 119, 772-787 (2009
137. Flozak, A. S. et al. β-catenin/T cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells. J. Biol. Chem. 285, 3157-3167 (2010
138. Ulsamer, A. et al. Axin pathway activity regulates in vivo pY654 β catenin accumulation and pulmonary fibrosis. J. Biol. Chem. 287, 5164-5172 (2012
139. Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF β mediated fibrosis. Nature Commun. 3, 735 (2012
140. Tanjore, H. et al. β catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am. J. Respir. Crit. Care Med. 187, 630-639 (2013
141. Gottardi, C. J. & Knigshoff, M. Considerations for targeting β catenin signaling in fibrosis. Am. J. Respir. Crit. Care Med. 187, 566-568 (2013
142. Dravid, G. et al. Defining the role of Wnt/β-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 23, 1489-1501 (2005
143. Qyang, Y. et al. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/β-catenin pathway. Cell Stem Cell 1, 165-179 (2007
144. Saraswati, S. et al. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post MI cardiac remodeling. PLoS ONE 5, e15521 (2010
145. Sasaki, T., Hwang, H., Nguyen, C., Kloner, R. A. & Kahn, M. The small molecule Wnt signaling modulator ICG 001 improves contractile function in chronically infarcted rat myocardium. PLoS ONE 8, e75010 (2013
146. de Lau, W., Peng, W. C., Gros, P. & Clevers, H. The R spondin/Lgr5/Rnf43 module: Regulator of Wnt signal strength. Genes Dev. 28, 305-316 (2014
147. de Lau, W. B. M., Snel, B. & Clevers, H. C. The R spondin protein family. Genome Biol. 13, 242 (2012
148. Zhao, J. et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132, 1331-1343 (2007
149. Bhanja, P. et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE 4, e8014 (2009
150. Zhou, W. J., Geng, Z. H., Spence, J. R. & Geng, J. G. Induction of intestinal stem cells by R spondin 1 and Slit2 augments chemoradioprotection. Nature 50, 107-111 (2013
151. Yu, Q., Sharma, A. & Sen, J. M. TCF1 and β-catenin regulate T cell development and function. Immunol. Res. 47, 45-55 (2010
152. Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Med. 15, 808-813 (2009
153. Jeannet, G. et al. Essential role of the Wnt pathway effector Tcf 1 for the establishment of functional CD8 T cell memory. Proc. Natl Acad. Sci. USA 107, 9777-9782 (2010
154. Zhao, D. M. et al. Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J. Immun. 184, 1191-11989 (2010
155. Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229-240 (2010
156. Notani, D. et al. Global regulator SATB1 recruits β-catenin and regulates TH2 differentiation in Wnt-dependent manner. PLoS Biol. 8, e1000296 (2010
157. Ding, Y., Shen, S., Lino, A. C., Curotto de Lafaille, M. A. & Lafaille, J. J. β-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nature Med. 14, 162-169 (2008
158. Sen, M. et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 2791-2796 (2000
159. Nakamura, Y., Nawata, M. & Wakitani, S. Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am. J. Pathol. 167, 97-105 (2005
160. Keerthivasan, S. et al. β-catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T Cells. Sci. Transl. Med. 6, 225ra28 (2014
161. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nature Immunol. 10, 734-743 (2009
162. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113 (2007
163. Garca-Jimnez, C. Wnt and incretin connections. Vitam. Horm. 84, 355-387 (2010
164. Abiola, M. et al. Activation of Wnt/β-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP 1c in skeletal muscle cells. PLoS ONE 4, e8509 (2009
165. Welters, H. J. & Kulkarni, R. N. Wnt signaling: Relevance to β-cell biology and diabetes. Trends Endocrinol. Metab. 19, 349-355 (2008
166. Grant, S. F. et al. Variant of transcription factor 7 like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320-323 (2006
167. Takamoto, I. et al. TCF7L2 in mouse pancreatic β cells plays a crucial role in glucose homeostasis by regulating β cell mass. Diabetologia 57, 542-553 (2014
168. Aly, H. et al. A novel strategy to increase the proliferative potential of adult human β cells while maintaining their differentiated phenotype. PLoS ONE 8, e66131 (2013
169. Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080-1086 (2006
170. Hernandez, L. et al. Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria. Dev. Cell 19, 413-425 (2010
171. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803-806 (2007
172. Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807-810 (2007
173. Bernard, P. & Harley, V. R. Wnt4 action in gonadal development and sex determination. Int. J. Biochem. Cell Biol. 39, 31-43 (2007
174. Lear, J. T. Oral hedgehog-pathway inhibitors for basal-cell carcinoma. N. Engl. J. Med. 366, 2225-2226 (2012
175. Sakata, T. & Chen, J. K. Chemical 'Jekyll and Hyde's: Small-molecule inhibitors of developmental signaling pathways. Chem. Soc. Rev. 40, 4318-4331 (2011
176. White, B. D. et al. β-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-Traumatic gliogenesis in the adult brain. Stem Cells 28, 297-307 (2010
177. Fancy, S. P. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nature Neurosci. 14, 1009-1016 (2011
178. Previdi, S. et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/ Wnt pathways. Eur. J. Cancer 46, 1679-1691 (2010
179. Kajiguchi, T. et al. FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia 21, 2476-2484 (2007
180. Kajiguchi, T. et al. Y654 of β catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β catenin. Eur. J. Haematol. 88, 314-320 (2012
181. Zhou, L. et al. Tyrosine kinase inhibitor STI 571/Gleevec down-regulates the β-catenin signaling activity. Cancer Lett. 193, 161-170 (2003
182. Christensen, J. G. et al. A selective small molecule inhibitor of c Met kinase inhibits c Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63, 7345-7355 (2003
183. Hayward, P. et al. Notch modulates Wnt signalling by associating with Armadillo/β-catenin and regulating its transcriptional activity. Development 132, 1819-1830 (2005
184. Bertrand, F. E., Angus, C. W., Partis, W. J. & Sigounas, G. Developmental pathways in colon cancer: Crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle 11, 4344-4351 (2012
185. Lukaszewicz, A. I., McMillan, M. K. & Kahn, M. Small molecules and stem cells. Potency and lineage commitment: The new quest for the fountain of youth. J. Med. Chem. 53, 3439-3453 (2010
186. Yao, J. et al. Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β catenin. Cancer Biol. Ther. 14, 833-839 (2013
187. Janssen, K. P. et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131, 1096-1109 (2003
188. Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122-14127 (2006
189. Harada, N. et al. Hepatocarcinogenesis in mice with β-catenin and Ha-Ras gene mutations. Cancer Res. 64, 48-54 (2004
190. Kerkhoff, E. et al. Regulation of c myc expression by Ras/Raf signalling. Oncogene 16, 211-216 (1998
191. Araki, Y. et al. Regulation of cyclooxygenase 2 expression by the Wnt and Ras pathways. Cancer Res. 63, 728-734 (2003
192. Masckauchn, T. N., Shawber, C. J., Funahashi, Y., Li, C. M. & Kitajewski, J. Wnt/β-catenin signaling induces proliferation, survival and interleukin 8 in human endothelial cells. Angiogenesis 8, 43-51 (2005
193. Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: Two sides of a coin. Science 307, 1904-1909 (2005
194. Corada, M. et al. The Wnt/β-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev. Cell 18, 938-949 (2010
195. Aulehla, A. et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395-406 (2003
196. Miyabayashi, T. et al. Wnt/β-catenin/CBP signaling maintains long-Term murine embryonic stem cell pluripotency. Proc. Natl Acad. Sci. USA 104, 5668-5673 (2007
197. Hasegawa, K. et al. Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-Term xeno-free human pluripotent cell expansion. Stem Cells Transl. Med. 1, 18-28 (2012
198. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-Throughput screening. Cell 138, 645-659 (2009
199. Lu, D. et al. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc. Natl Acad. Sci. USA 108, 13253-13257 (2011
200. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on Development. Proc. Natl Acad. Sci. USA 93, 8455-8459 (1996
201. Giardiello, F. M. et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N. Engl. J. Med. 328, 131-136 (1993
202. Schreinemachers, D. M. & Everson, R. B. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemeology 5, 138-146 (1994
203. Dihlmann, S., Siermann, A. & von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF 4 signaling. Oncogene 20, 645-653 (2001
204. Thun, M. J., Henley, S. J. & Patrono, C. Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J. Natl Cancer. Inst. 94, 252-266 (2002
205. Sandler, R. S. et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med. 348, 883-890 (2003
206. Baron, J. A. et al. A randomized trial of aspirin to prevent colorectal adenomas. N. Engl. J. Med. 348, 891-899 (2003
207. Boon, E. M. et al. Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br. J. Cancer 90, 224-229 (2004
208. Grsch, S., Tegeder, I., Niederberger, E., Brδutigam, L. & Geisslinger, G. COX 2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX 2 inhibitor celecoxib. FASEB J. 15, 2742-2744 (2001
209. Maier, T. J., Janssen, A., Schmidt, R., Geisslinger, G. & Grsch, S. Targeting the β-catenin/APC pathway: A novel mechanism to explain the cyclooxygenase 2 independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB J. 19, 1353-1355 (2005
210. Phillips, R. K. et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on Duodenal polyposis in familial adenomatous polyposis. Gut 50, 857-860 (2002
211. Shah, S., Hecht, A., Pestell, R. & Byers, S. W. Trans-repression of β-catenin activity by nuclear receptors. J. Biol. Chem. 278, 48137-48145 (2003
212. Plmer, H. G. et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E cadherin and the inhibition of β-catenin signaling. J. Cell Biol. 154, 369-387 (2001
213. Pends-Franco, N. et al. Vitamin D and Wnt/β-catenin pathway in colon cancer: Role and regulation of DICKKOPF genes. Anticancer Res. 28, 2613-2623 (2008
214. Rao, C. V. et al. Chemoprevention of colon carcinogenesis by phenylethyl 3 methylcaffeate. Cancer Res. 55, 2310-2315 (1995
215. Jaiswal, A. S., Marlow, B. P., Gupta, N. & Narayan, S. β-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 8414-8427 (2002
216. Park, C. H. et al. Quercetin, a potent inhibitor against β-catenin/Tcf signaling in SW480 colon cancer cells. Biochem. Biophys. Res. Commun. 328, 227-234 (2005
217. Kim, J. et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3 gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J. Biol. Chem. 281, 10865-10875 (2006
218. Roccaro, A. M. et al. Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrm's macroglobulinemia. Clin. Cancer Res. 14, 1849-1858 (2008
219. Funato, Y., Michiue, T., Asashima, M. & Miki, H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-β-catenin signalling through dishevelled. Nature Cell. Biol. 8, 501-508 (2006
220. Antelmann, H. & Helmann, J. D. Thiol-based redox switches and gene regulation. Antioxid. Redox. Signal. 14, 1049-1063 (2011
221. Thorne, C. A. et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1. Nature Chem. Biol. 6, 829-836 (2010
222. Lepourcelet, M. et al. Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Cancer Cell 5, 91-102 (2004
223. Gonsalves, F. C. et al. An. RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc. Natl Acad. Sci. USA 108, 5894-5863 (2011
224. Chen, Z. et al. 2,4 diamino-quinazolines as inhibitors of β-catenin/Tcf 4 pathway: Potential treatment for colorectal cancer. Bioorg. Med. Chem. Lett. 19, 4980-4983 (2009
225. Trosset, J. Y. et al. Inhibition of protein-protein interactions: The discovery of druglike β-catenin inhibitors by combining virtual and biophysical screening. Proteins 64, 60-67 (2006
226. Tian, W. et al. Structure-based discovery of a novel inhibitor targeting the β catenin/Tcf4 interaction. Biochemistry 51, 724-731 (2012
227. Hahne, G. & Grossmann, T. N. Direct targeting of β catenin: Inhibition of protein-protein interactions for the inactivation of Wnt signaling. Bioorg. Med. Chem. 21, 4020-4026 (2013
228. Takada, K. et al. Targeted disruption of the BCL9/ β catenin complex inhibits oncogenic Wnt signaling. Sci. Transl. Med. 4, 148ra117 (2012
229. Grossmann, T. N. et al. Inhibition of oncogenic Wnt signaling through direct targeting of β catenin. Proc. Natl Acad. Sci. USA 109, 17942-17947 (2012
230. Shan, J., Shi, D. L., Wang, J. & Zheng, J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44, 15495-15503 (2005
231. Fujii, N. et al. An antagonist of dishevelled protein-protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67, 573-579 (2007
232. Grandy, D. et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284, 16256-16263 (2009
233. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chem. Biol. 5, 100-107 (2009
234. Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614-620 (2009
235. Lehti, L., Chi, N. W. & Krauss, S. Tankyrases as drug targets. FEBS J. 280, 3576-3593 (2013
236. Lau, T. et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 73, 3132-3144 (2013
237. Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R spondin-sensitive manner. Nature 485, 195-200 (2012
238. Jacob, L. S. et al. Genome-wide RNAi screen reveals disease-Associated genes that are common to Hedgehog and Wnt signaling. Sci. Signal. 4, ra4 (2011
239. Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665-669 (2012
240. Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 12649-12654 (2013
241. Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis. Oncogene 27, 7118-7130 (2008
242. Wei, W., Chua, M. S., Grepper, S. & So, S. K. Soluble Frizzled 7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin. Mol. Cancer 10, 16 (2011
243. Pode-Shakked, N. et al. Resistance or sensitivity of Wilms' tumor to anti FZD7 antibody highlights the Wnt pathway as a possible therapeutic target. Oncogene 30, 1664-1680 (2011
244. Gurney, A. et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in Decreased growth and tumorigenicity of human tumors. Proc. Natl Acad. Sci. USA 109, 11717-11722 (2012
245. Kung, A. L. et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14, 272-277 (2000
246. Yamauchi, T. et al. Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nature Genet. 30, 221-226 (2002
247. Roth, J. F. et al. Differential role of p300 and CBP acetyltransferase during myogenesis: 300 acts upstream of MyoD and Myf5. EMBO J. 22, 5186-5196 (2003
248. McMillan, M. & Kahn, M. Investigating Wnt signaling: A chemogenomic safari. Drug Discov. Today 10, 1467-1474 (2005
249. Emami, K. H. et al. A small molecule inhibitor of β-catenin/CREB- binding protein transcription [corrected]. Proc. Natl Acad. Sci. USA 101, 12682-12687 (2004
250. Marson, A. et al. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3, 132-135 (2008
251. Schenke-Layland, K. et al. Recapitulation of the embryonic cardiovascular progenitor cell niche. Biomaterials 2, 2748-2756 (2011
252. Wend, P. et al. Wnt/β catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J. 32, 1977-1989 (2013
253. Gang, E. J. et al. Small-molecule inhibition of CBP/ catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 33, 2169-2178 (2013
254. He, K. et al. Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β catenin/CBP pathway. Int. J. Cancer 134, 43-54 (2014
255. Kahn, M. Symmetric division versus asymmetric division: A tale of two coactivators. Future Med. Chem. 3, 1745-1763 (2011
256. Takada, R. et al. Monounsaturated fatty acid modification of Wnt protein: Its role in Wnt secretion. Dev. Cell 11, 791-801 (2006
257. Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224-20229 (2013
258. Smith, D. C. et al. First in human evaluation of the human monoclonal antibody vantictumab (OMP 18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J. Clin. Oncol. Abstr. 31, 2540 (2013
259. Morishita, E. C. et al. Crystal structures of the armadillo repeat domain of adenomatous polyposis coli and its complex with the tyrosine-rich domain of Sam68. Structure 19, 1496-1508 (2011
260. Ma, H., Nguyen, C., Lee., K. S. & Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene 24, 3619-3631 (2005
261. el Khoueiry, A. et al. A phase I first in human study of PRI 724 in patients (pts) with advanced solid tumors. J. Clin. Oncol. Abstr. 31, 2501 (2013
262. Mahmoudi, T. et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 28, 3329-3340 (2009
263. Shitashige, M. et al. Traf2- And Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 70, 5024-5033 (2010
264. Onder, T. T. et al. Loss of E cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645-3654 (2008
265. Kim, K., Daniels, K. J. & Hay, E. D. Tissue-specific expression of β-catenin in normal mesenchyme and uveal melanomas and its effect on invasiveness. Exp. Cell Res. 245, 79-90 (1998
266. Valastyan, S. & Weinberg, R. A. Tumor metastasis: Molecular insights and evolving paradigms. Cell 147, 275-292 (2011
267. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008
268. Wagh, P. K. et al. β catenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene 30, 3694-3704 (2011
269. Coluccia, A. M. et al. SKI 606 decreases growth and motility of colorectal cancer cells by preventing pp60(c Src)-dependent tyrosine phosphorylation of β-catenin and its nuclear signaling. Cancer Res. 66, 2279-2286 (2006
270. Ress, A. & Moelling, K. Bcr interferes with β-catenin- Tcf1 interaction. FEBS Lett. 580, 1227-1230 (2006
271. Fujino, H., West, K. A. & Regan, J. W. Phosphorylation of glycogen synthase kinase 3 and stimulation of T cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. J. Biol. Chem. 277, 2614-2619 (2002
272. Fujino, H. & Regan, J. W. FP prostanoid receptor activation of a T cell factor/β-catenin signaling pathway. J. Biol. Chem. 276, 12489-12492 (2001
273. Liu, X., Rubin, J. S. & Kimmel, A. R. Rapid, Wnt-induced changes in GSK3β associations that regulate β-catenin stabilization are mediated by Gα proteins. Curr. Biol. 15, 1989-1997 (2005
274. Meigs, T. E., Fields, T. A., McKee, D. D. & Casey, P. J. Interaction of Gα12 and Gα13 with the cytoplasmic domain of cadherin provides a mechanism for β-catenin release. Proc. Natl Acad. Sci. USA 98, 519-524 (2001
275. Mazumdar, J. et al. O2 regulates stem cells through Wnt/β catenin signalling. Nature Cell Biol. 12, 1007-1013 (2010
276. Chocarro-Calvo, A., Garca-Martnez, J. M., Ardila-Gonzαlez, S., De la Vieja, A. & Garca-Jimnez, C. Glucose-induced β catenin acetylation enhances Wnt signaling in cancer. Mol. Cell 49, 474-486 (2013
277. Gσmez-Orte, E., Sαenz-Narciso, B., Moreno, S. & Cabello, J. Multiple functions of the noncanonical Wnt pathway. Trends Genet. 29, 545-553 (2013
278. Tada, M. & Kai, M. Noncanonical Wnt/PCP signaling during vertebrate gastrulation. Zebrafish 6, 29-40 (2009
279. Wang, Y. Wnt/planar cell polarity signaling: A new paradigm for cancer therapy. Mol. Cancer Ther. 8, 2103-2109 (2009
280. Lai, S. L., Chien, A. J. & Moon, R. T. Wnt/Fz signaling and the cytoskeleton: Potential roles in tumorigenesis. Cell Res. 19, 532-545 (2009
281. Ginis, I. et al. Differences between human and mouse embryonic stem cells. Dev. Biol. 269, 360-380 (2004
282. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK 3 specific inhibitor. Nature Med. 10, 55-63 (2004
283. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001
284. Otero, J. J., Fu, W., Kan, L., Cuadra, A. E. & Kessler, J. A. β-catenin signaling is required for neural differentiation of embryonic stem cells. Development 131, 3545-3557 (2004
285. Faunes, F. et al. A membrane-Associated β catenin/ Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Development 140, 1171-1183 (2013
286. Zechner, D. et al. β-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev. Biol. 258, 406-418 (2003
287. Hari, L. et al. Lineage-specific requirements of β-catenin in neural crest development. J. Cell Biol. 159, 867-880 (2002
288. Muroyama, Y., Kondoh, H. & Takada, S. Wnt proteins promote neuronal differentiation in neural stem cell culture. Biochem. Biophys. Res. Commun. 313, 915-921 (2004
289. LaBarge, M. The difficulty of targeting cancer stem cell niches. Clin. Cancer Res. 16, 3121-3129 (2010
290. Merchan, A. A. & Matsui, W. Targeting Hedgehog - A cancer stem cell pathway. Clin. Cancer Res. 16, 3130-3140 (2010
291. Pannuti, A. et al. Targeting Notch to target cancer stem cells. Clin. Cancer Res. 16, 3141-3152 (2010
292. Holland, J. D., Klaus, A., Garratt, A. N. & Birchmeier, W. Wnt signaling in stem and cancer stem cells. Curr. Opin. Cell Biol. 25, 254-264 (2013
293. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083-1095 (2009
294. Takahashi-Yanaga, F. & Kahn, M. Targeting Wnt signaling: Can we safely eradicate cancer stem cells?. Clin. Cancer Res. 16, 3153-3162 (2010