| Structural highlights
Disease
[CTNB1_HUMAN] Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:114500]. Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life. Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:132600]; a common benign skin tumor.[1] [2] [3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4] [5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1. Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.[6]
Function
[CTNB1_HUMAN] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.[7] [8] [9] [10] [T7L1A_XENLA] Participates in the Wnt signaling pathway. Binds to DNA and acts as a repressor in the absence of ctnnb1-A and possibly ctnnb1-B, and as an activator in the presence of these proteins. Required early in development for the establishment of the dorsal body axis in response to maternal Wnt signaling. Also required during development of the CNS for the establishment of dorsal-ventral patterning in the prospective diencephalon.[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Wnt signaling pathway plays critical roles in embryonic development and tumorigenesis. Stimulation of the Wnt pathway results in the accumulation of a nuclear beta-catenin/Tcf complex, activating Wnt target genes. A crystal structure of beta-catenin bound to the beta-catenin binding domain of Tcf3 (Tcf3-CBD) has been determined. The Tcf3-CBD forms an elongated structure with three binding modules that runs antiparallel to beta-catenin along the positively charged groove formed by the armadillo repeats. Structure-based mutagenesis defines three sites in beta-catenin that are critical for binding the Tcf3-CBD and are differentially involved in binding APC, cadherin, and Axin. The structural and mutagenesis data reveal a potential target for molecular drug design studies.
Crystal structure of a beta-catenin/Tcf complex.,Graham TA, Weaver C, Mao F, Kimelman D, Xu W Cell. 2000 Dec 8;103(6):885-96. PMID:11136974[28]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Moreno-Bueno G, Gamallo C, Perez-Gallego L, Contreras F, Palacios J. beta-catenin expression in pilomatrixomas. Relationship with beta-catenin gene mutations and comparison with beta-catenin expression in normal hair follicles. Br J Dermatol. 2001 Oct;145(4):576-81. PMID:11703283
- ↑ van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
- ↑ Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999 Apr;21(4):410-3. PMID:10192393 doi:10.1038/7747
- ↑ van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
- ↑ Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000 Feb;156(2):433-7. PMID:10666372
- ↑ Shigemitsu K, Sekido Y, Usami N, Mori S, Sato M, Horio Y, Hasegawa Y, Bader SA, Gazdar AF, Minna JD, Hida T, Yoshioka H, Imaizumi M, Ueda Y, Takahashi M, Shimokata K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene. 2001 Jul 12;20(31):4249-57. PMID:11464291 doi:10.1038/sj.onc.1204557
- ↑ Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
- ↑ Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 2008 Jan 1;22(1):91-105. Epub 2007 Dec 17. PMID:18086858 doi:10.1101/gad.1596308
- ↑ Li H, Ray G, Yoo BH, Erdogan M, Rosen KV. Down-regulation of death-associated protein kinase-2 is required for beta-catenin-induced anoikis resistance of malignant epithelial cells. J Biol Chem. 2009 Jan 23;284(4):2012-22. doi: 10.1074/jbc.M805612200. Epub 2008, Oct 27. PMID:18957423 doi:10.1074/jbc.M805612200
- ↑ Fiset A, Xu E, Bergeron S, Marette A, Pelletier G, Siminovitch KA, Olivier M, Beauchemin N, Faure RL. Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. Cell Signal. 2011 May;23(5):911-9. doi: 10.1016/j.cellsig.2011.01.019. Epub 2011 , Jan 22. PMID:21262353 doi:10.1016/j.cellsig.2011.01.019
- ↑ Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell. 1996 Aug 9;86(3):391-9. PMID:8756721
- ↑ Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D. A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev. 1997 Sep 15;11(18):2359-70. PMID:9308964
- ↑ Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destree O, Clevers H. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature. 1998 Oct 8;395(6702):608-12. PMID:9783587 doi:10.1038/26989
- ↑ Brannon M, Brown JD, Bates R, Kimelman D, Moon RT. XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development. Development. 1999 Jun;126(14):3159-70. PMID:10375506
- ↑ McGrew LL, Takemaru K, Bates R, Moon RT. Direct regulation of the Xenopus engrailed-2 promoter by the Wnt signaling pathway, and a molecular screen for Wnt-responsive genes, confirm a role for Wnt signaling during neural patterning in Xenopus. Mech Dev. 1999 Sep;87(1-2):21-32. PMID:10495268
- ↑ Marikawa Y, Elinson RP. Relationship of vegetal cortical dorsal factors in the Xenopus egg with the Wnt/beta-catenin signaling pathway. Mech Dev. 1999 Dec;89(1-2):93-102. PMID:10559484
- ↑ Hamilton FS, Wheeler GN, Hoppler S. Difference in XTcf-3 dependency accounts for change in response to beta-catenin-mediated Wnt signalling in Xenopus blastula. Development. 2001 Jun;128(11):2063-73. PMID:11493528
- ↑ Darken RS, Wilson PA. Axis induction by wnt signaling: Target promoter responsiveness regulates competence. Dev Biol. 2001 Jun 1;234(1):42-54. PMID:11356018 doi:10.1006/dbio.2001.0253
- ↑ Lee E, Salic A, Kirschner MW. Physiological regulation of [beta]-catenin stability by Tcf3 and CK1epsilon. J Cell Biol. 2001 Sep 3;154(5):983-93. Epub 2001 Aug 27. PMID:11524435 doi:10.1083/jcb.200102074
- ↑ Snider L, Thirlwell H, Miller JR, Moon RT, Groudine M, Tapscott SJ. Inhibition of Tcf3 binding by I-mfa domain proteins. Mol Cell Biol. 2001 Mar;21(5):1866-73. PMID:11238923 doi:10.1128/MCB.21.5.1866-1873.2001
- ↑ Roel G, Hamilton FS, Gent Y, Bain AA, Destree O, Hoppler S. Lef-1 and Tcf-3 transcription factors mediate tissue-specific Wnt signaling during Xenopus development. Curr Biol. 2002 Nov 19;12(22):1941-5. PMID:12445388
- ↑ Houston DW, Kofron M, Resnik E, Langland R, Destree O, Wylie C, Heasman J. Repression of organizer genes in dorsal and ventral Xenopus cells mediated by maternal XTcf3. Development. 2002 Sep;129(17):4015-25. PMID:12163405
- ↑ Rex M, Hilton E, Old R. Multiple interactions between maternally-activated signalling pathways control Xenopus nodal-related genes. Int J Dev Biol. 2002 Mar;46(2):217-26. PMID:11934150
- ↑ Hilton E, Rex M, Old R. VegT activation of the early zygotic gene Xnr5 requires lifting of Tcf-mediated repression in the Xenopus blastula. Mech Dev. 2003 Oct;120(10):1127-38. PMID:14568102
- ↑ Hikasa H, Sokol SY. The involvement of Frodo in TCF-dependent signaling and neural tissue development. Development. 2004 Oct;131(19):4725-34. Epub 2004 Aug 25. PMID:15329348 doi:10.1242/dev.01369
- ↑ Tsuji S, Hashimoto C. Choice of either beta-catenin or Groucho/TLE as a co-factor for Xtcf-3 determines dorsal-ventral cell fate of diencephalon during Xenopus development. Dev Genes Evol. 2005 Jun;215(6):275-84. Epub 2005 Mar 4. PMID:15747128 doi:10.1007/s00427-005-0474-0
- ↑ Snider L, Tapscott SJ. XIC is required for Siamois activity and dorsoanterior development. Mol Cell Biol. 2005 Jun;25(12):5061-72. PMID:15923623 doi:25/12/5061
- ↑ Graham TA, Weaver C, Mao F, Kimelman D, Xu W. Crystal structure of a beta-catenin/Tcf complex. Cell. 2000 Dec 8;103(6):885-96. PMID:11136974
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