BioPAX pathway converted from "RUNX3 binds CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)" in the Reactome database.RUNX3 binds CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)

RUNX3 binds CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)

RUNX3 forms a ternary complex with beta-catenin (CTNNB1) and its binding partner TCF7L2 (TCF4). In addition to TCF7L2, RUNX3 is also able to interact with LEF1, TCF7L1 (TCF3) and TCF7 (also known as TCF1). The interaction involves the Runt domain of RUNX3 and the HMG box of TCF7L2 (Ito et al. 2008).

Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31

Reactome DB_ID: 8951429

nucleoplasmGO0005654CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7) [nucleoplasm]

CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)

CTNNB1:TCF4,(LEF1,TCF3,TCF1)

Reactome DB_ID: 3451168

UniProt:P35222 CTNNB1

CTNNB1

CTNNBOK/SW-cl.35CTNNB1PRO2286FUNCTION 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, TBP, 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).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. Phosphorylation proceeds then from Thr-41 to Ser-37 and Ser-33. Phosphorylated by NEK2. EGF stimulates tyrosine phosphorylation. Phosphorylation on Tyr-654 decreases CDH1 binding and enhances TBP binding. Phosphorylated on Ser-33 and Ser-37 by HIPK2 and GSK3B, this phosphorylation triggers proteasomal degradation (PubMed:25169422). Phosphorylation on Ser-191 and Ser-246 by CDK5. Phosphorylation by CDK2 regulates insulin internalization. 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.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.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtP35222

Chain Coordinates

EQUAL

781

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 8951427

TCF7L2,(LEF1,TCF7L1,TCF7) [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTCF7L2 [nucleoplasm]

UniProtQ9NQB0Reactome Database ID Release 758951429Database 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=8951429ReactomeR-HSA-8951429

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-8951429.1

Reactome DB_ID: 8865393

UniProt:Q13761 RUNX3

RUNX3

CBFA3PEBP2A3AML2RUNX3FUNCTION Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (By similarity). May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, upregulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity).SUBUNIT Heterodimer with CBFB. RUNX3 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization (By similarity). Interacts with TLE1 and SUV39H1 (PubMed:9751710 and PubMed:16652147). The tyrosine phosphorylated form (via runt domain) interacts with SRC (via protein kinase domain)(PubMed:20100835). Interacts with FYN and LCK (PubMed:20100835). Interacts with FOXP3 (PubMed:17377532). Interacts with ZFHX3 (PubMed:20599712). Interacts with TBX21 (By similarity).TISSUE SPECIFICITY Expressed in gastric cancer tissues (at protein level).DOMAIN A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.PTM Phosphorylated on tyrosine residues by SRC. Phosphorylated by LCK and FYN.

UniProtQ13761

EQUAL

415

EQUAL

Reactome DB_ID: 8951432

RUNX3:CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7) [nucleoplasm]

RUNX3:CTNNB1:TCF7L2,(LEF1,TCF7L1,TCF7)

RUNX3:CTNNB1:TCF4,(LEF1,TCF3,TCF1)

Reactome DB_ID: 8951429

Reactome DB_ID: 8865393

EQUAL

415

EQUAL

Reactome Database ID Release 758951432Database 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=8951432ReactomeR-HSA-8951432

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-8951432.2Reactome Database ID Release 758951428Database 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=8951428ReactomeR-HSA-8951428

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-8951428.218772112Pubmed2008RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesisIto, KoseiLim, Anthony Chee-BengSalto-Tellez, ManuelMotoda, LenaOsato, MotomiChuang, Linda Shyue HueyLee, Cecilia Wei LinVoon, Dominic Chih-ChengKoo, Jason Kin WaiWang, HuajingFukamachi, HiroshiIto, YoshiakiCancer Cell 14:226-37