| 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
[FBW1A_HUMAN] Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds to phosphorylated target proteins. SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling. SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22'. SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, SMAD3, SMAD4, CDC25A, DLG1, FBXO5 and probably NFKB2. SCF(BTRC) mediates the ubiquitination of phosphorylated SNAI1. May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3.[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [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.[22] [23] [24] [25] [SKP1_HUMAN] Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.[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 SCF ubiquitin ligases catalyze protein ubiquitination in diverse cellular processes. SCFs bind substrates through the interchangeable F box protein subunit, with the >70 human F box proteins allowing the recognition of a wide range of substrates. The F box protein beta-TrCP1 recognizes the doubly phosphorylated DpSGphiXpS destruction motif, present in beta-catenin and IkappaB, and directs the SCF(beta-TrCP1) to ubiquitinate these proteins at specific lysines. The 3.0 A structure of a beta-TrCP1-Skp1-beta-catenin complex reveals the basis of substrate recognition by the beta-TrCP1 WD40 domain. The structure, together with the previous SCF(Skp2) structure, leads to the model of SCF catalyzing ubiquitination by increasing the effective concentration of the substrate lysine at the E2 active site. The model's prediction that the lysine-destruction motif spacing is a determinant of ubiquitination efficiency is confirmed by measuring ubiquitination rates of mutant beta-catenin peptides, solidifying the model and also providing a mechanistic basis for lysine selection.
Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.,Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP Mol Cell. 2003 Jun;11(6):1445-56. PMID:12820959[28]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature. 1998 Dec 10;396(6711):590-4. PMID:9859996 doi:10.1038/25159
- ↑ Suzuki H, Chiba T, Kobayashi M, Takeuchi M, Suzuki T, Ichiyama A, Ikenoue T, Omata M, Furuichi K, Tanaka K. IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2. Biochem Biophys Res Commun. 1999 Mar 5;256(1):127-32. PMID:10066435 doi:10.1006/bbrc.1999.0289
- ↑ Shirane M, Hatakeyama S, Hattori K, Nakayama K, Nakayama K. Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1. J Biol Chem. 1999 Oct 1;274(40):28169-74. PMID:10497169
- ↑ Orian A, Gonen H, Bercovich B, Fajerman I, Eytan E, Israel A, Mercurio F, Iwai K, Schwartz AL, Ciechanover A. SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. EMBO J. 2000 Jun 1;19(11):2580-91. PMID:10835356 doi:10.1093/emboj/19.11.2580
- ↑ Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K. Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. J Biol Chem. 2000 Jan 28;275(4):2877-84. PMID:10644755
- ↑ Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol Biol Cell. 2001 May;12(5):1431-43. PMID:11359933
- ↑ Lassot I, Segeral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol. 2001 Mar;21(6):2192-202. PMID:11238952 doi:10.1128/MCB.21.6.2192-2202.2001
- ↑ Fong A, Sun SC. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100. J Biol Chem. 2002 Jun 21;277(25):22111-4. Epub 2002 May 6. PMID:11994270 doi:10.1074/jbc.C200151200
- ↑ Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK. Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell. 2003 Jun;4(6):813-26. PMID:12791267
- ↑ Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 2003 Dec 15;17(24):3062-74. Epub 2003 Dec 17. PMID:14681206 doi:10.1101/gad.1157503
- ↑ Mantovani F, Banks L. Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor. J Biol Chem. 2003 Oct 24;278(43):42477-86. Epub 2003 Aug 5. PMID:12902344 doi:http://dx.doi.org/10.1074/jbc.M302799200
- ↑ Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF. Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature. 2003 Nov 6;426(6962):87-91. PMID:14603323 doi:10.1038/nature02082
- ↑ Wan M, Tang Y, Tytler EM, Lu C, Jin B, Vickers SM, Yang L, Shi X, Cao X. Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J Biol Chem. 2004 Apr 9;279(15):14484-7. Epub 2004 Feb 26. PMID:14988407 doi:10.1074/jbc.C400005200
- ↑ Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004 Oct;6(10):931-40. Epub 2004 Sep 26. PMID:15448698 doi:10.1038/ncb1173
- ↑ Wang B, Li Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):33-8. Epub 2005 Dec 21. PMID:16371461 doi:10.1073/pnas.0509927103
- ↑ 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
- ↑ Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941 doi:10.1016/j.molcel.2005.09.003
- ↑ Li Y, Hao B. Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase. J Biol Chem. 2010 Apr 30;285(18):13896-906. Epub 2010 Feb 24. PMID:20181953 doi:10.1074/jbc.M110.111518
- ↑ Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell. 2003 Jun;11(6):1445-56. PMID:12820959
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