BioPAX pathway converted from "Beta-catenin migrates to the nucleus" in the Reactome database. Beta-catenin migrates to the nucleus Beta-catenin migrates to the nucleus Phosphorylated beta-catenin migrates to the nucleus where it functions as a coactivator of IRF3-dependent transcription (Yang P et al. 2010).<p>Beta-catenin transport to the nucleus is thought to occur in a NLS (nuclear localization signal)- and importin-independent manner through direct interaction with the nuclear pore complex (NPC) components. This has been shown to be the case for Wnt-signaling in mammalian cells (Yokoya F et al. 1999; Koike M et al. 2004; Sharma M et al. 2012) Authored: Shamovsky, V, 2013-02-06 Reviewed: D'Eustachio, P, 2013-02-11 Reviewed: Jin, Lei, 2013-05-21 Reviewed: Wu, Jiaxi, 2013-05-21 Edited: Shamovsky, V, 2013-05-17 Reactome DB_ID: 3134933 1 cytosol GO 0005829 UniProt:P35222 CTNNB1 CTNNB1 CTNNB OK/SW-cl.35 CTNNB1 PRO2286 FUNCTION Key downstream component of the canonical Wnt signaling pathway (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). 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 (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). 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 (PubMed:17524503, PubMed:18077326, PubMed:18086858, PubMed:18957423, PubMed:21262353, PubMed:22155184, PubMed:22647378, PubMed:22699938). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion (PubMed:18086858). Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization (PubMed:21262353). Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2 (PubMed:18957423). Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (PubMed:22155184). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle (By similarity). Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity).SUBUNIT Two separate complex-associated pools are found in the cytoplasm. The majority is present as component of an E-cadherin:catenin adhesion complex composed of at least E-cadherin/CDH1 and beta-catenin/CTNNB1, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1. Another cytoplasmic pool is part of a large complex containing 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. Wnt-dependent activation of DVL antagonizes the action of GSK3B. When GSK3B activity is inhibited the complex dissociates, CTNNB1 is dephosphorylated and is no longer targeted for destruction. The stabilized protein translocates to the nucleus, where it binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Binds CTNNBIP and EP300. CTNNB1 forms a ternary complex with LEF1 and EP300 that is disrupted by CTNNBIP1 binding. Interacts with TAX1BP3 (via the PDZ domain); this interaction inhibits the transcriptional activity of CTNNB1. Interacts with AJAP1, BAIAP1, CARM1, CTNNA3, CXADR and PCDH11Y. Binds SLC9A3R1. Interacts with GLIS2 and MUC1. Interacts with SLC30A9. Interacts with XIRP1. Interacts directly with AXIN1; the interaction is regulated by CDK2 phosphorylation of AXIN1. Interacts with SCRIB. Interacts with RAPGEF2. Interacts with PTPRU (via the cytoplasmic juxtamembrane domain). Interacts with EMD. Interacts with TNIK and TCF7L2. Interacts with SESTD1 and TRPC4. Interacts with CAV1. Interacts with TRPV4. The TRPV4 and CTNNB1 complex can interact with CDH1. Interacts with VCL. Interacts with PTPRJ. Interacts with PKT7 and CDK2. Interacts with FAT1 (via the cytoplasmic domain). Interacts with NANOS1 and NDRG2. Interacts with isoform 1 of NEK2. Interacts with both isoform 1 and isoform 2 of CDK5. Interacts with PTK6. Interacts with SOX7; this interaction may lead to proteasomal degradation of active CTNNB1 and thus inhibition of Wnt/beta-catenin-stimulated transcription. Identified in a complex with HINT1 and MITF. Interacts with FHIT. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Interacts with FERMT2. Identified in a complex with TCF7L2/TCF4 and FERMT2 (PubMed:29739711, PubMed:22699938). Interacts with RORA. May interact with P-cadherin/CDH3. Interacts with RNF220 (PubMed:25266658). Interacts with CTNND2 (PubMed:25807484). Interacts (via the C-terminal region) with CBY1 (PubMed:12712206, PubMed:16424001). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (PubMed:25169422). Interacts with DLG5 (By similarity). Interacts with FAM53B; promoting translocation to the nucleus (PubMed:25183871). Interacts with TMEM170B (PubMed:29367600). Interacts with AHI1 (PubMed:21623382). Interacts with GID8 (PubMed:28829046). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (PubMed:28051089). Forms a complex comprising APPL1, RUVBL2, APPL2, HDAC1 and HDAC2 (PubMed:19433865). Interacts with IRF2BPL; mediates the ubiquitination and degradation of CTNNB1 (PubMed:29374064). Interacts with AMFR (By similarity). Interacts with LMBR1L (PubMed:31073040). Interacts with SOX30; prevents interaction of CTNNB1 with TCF7L2/TCF4 and leads to inhibition of Wnt signaling (PubMed:29739711). Interacts with SOX9; inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Interacts with SPN/CD43 cytoplasmic tail (PubMed:15003504). Interacts (when phosphorylated at Tyr-333) with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein vPK; this interaction inhibits the Wnt signaling pathway.TISSUE SPECIFICITY Expressed in several hair follicle cell types: basal and peripheral matrix cells, and cells of the outer and inner root sheaths. Expressed in colon. Present in cortical neurons (at protein level). Expressed in breast cancer tissues (at protein level) (PubMed:29367600).PTM Phosphorylation at Ser-552 by AMPK promotes stabilizion of the protein, enhancing TCF/LEF-mediated transcription (By similarity). Phosphorylation by GSK3B requires prior phosphorylation of Ser-45 by another kinase (PubMed:10966653, PubMed:12051714, PubMed:12027456). Phosphorylation proceeds then from Thr-41 to Ser-37 and Ser-33 (PubMed:12077367, PubMed:25169422). Phosphorylated by NEK2 (PubMed:18086858). EGF stimulates tyrosine phosphorylation (PubMed:10187801). Phosphorylated on Ser-33 and Ser-37 by HIPK2 and GSK3B, this phosphorylation triggers proteasomal degradation (PubMed:20307497). Phosphorylation on Ser-191 and Ser-246 by CDK5 (PubMed:17009320). Phosphorylation by CDK2 regulates insulin internalization (PubMed:21262353). Phosphorylation by PTK6 at Tyr-64, Tyr-142, Tyr-331 and/or Tyr-333 with the predominant site at Tyr-64 is not essential for inhibition of transcriptional activity (PubMed:20026641). Phosphorylation by SRC at Tyr-333 promotes interaction with isoform M2 of PKM (PKM2); promoting transcription activation (PubMed:22056988).PTM Ubiquitinated by the SCF(BTRC) E3 ligase complex when phosphorylated by GSK3B, leading to its degradation (PubMed:12077367). Ubiquitinated by a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X, leading to its subsequent proteasomal degradation (PubMed:11389839, PubMed:11389840, PubMed:20307497). Ubiquitinated and degraded following interaction with SOX9 (By similarity).PTM S-nitrosylation at Cys-619 within adherens junctions promotes VEGF-induced, NO-dependent endothelial cell permeability by disrupting interaction with E-cadherin, thus mediating disassembly adherens junctions.PTM O-glycosylation at Ser-23 decreases nuclear localization and transcriptional activity, and increases localization to the plasma membrane and interaction with E-cadherin CDH1.PTM Deacetylated at Lys-49 by SIRT1.DISEASE 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.DISEASE 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.SIMILARITY Belongs to the beta-catenin family.CAUTION A paper showing an interaction with TBP and phosphorylation at Tyr-86 and Tyr-654 has been retracted due to panel duplication in several figures. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt P35222 O-phospho-L-serine at 552 552 EQUAL O-phospho-L-serine [MOD:00046] Chain Coordinates 1 EQUAL 781 EQUAL Reactome DB_ID: 3134926 1 nucleoplasm GO 0005654 O-phospho-L-serine at 552 552 EQUAL 1 EQUAL 781 EQUAL Reactome Database ID Release 82 3134914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3134914 Reactome R-HSA-3134914 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3134914.1 20453844 Pubmed 2010 The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway Yang, Pengyuan An, Huazhang Liu, Xingguang Wen, Mingyue Zheng, Yuanyuan Rui, Yaocheng Cao, X Nat. Immunol. 11:487-94 22110128 Pubmed 2012 Specific armadillo repeat sequences facilitate ?-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358 Sharma, Manisha Jamieson, Cara Johnson, Michael Molloy, Mark P Henderson, Beric R J. Biol. Chem. 287:819-31 15173161 Pubmed 2004 beta-Catenin shows an overlapping sequence requirement but distinct molecular interactions for its bidirectional passage through nuclear pores Koike, Makiko Kose, Shingo Furuta, Maiko Taniguchi, Naoko Yokoya, Fumihiko Yoneda, Yoshihiro Imamoto, Naoko J. Biol. Chem. 279:34038-47