BioPAX pathway converted from "RUNX3 regulates YAP1-mediated transcription" in the Reactome database.RUNX3 regulates YAP1-mediated transcriptionRUNX3 regulates YAP1-mediated transcriptionAssociation of RUNX3 with the TEADs:YAP1 complex inhibits loading of the TEADs:YAP1 to the CTGF promoter, thus negatively regulating transcription of the CTGF gene which encodes the Connective tissue growth factor (Yagi et al. 1999, Zhao et al. 2008, Qiao et al. 2016).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31RUNX3 binds TEADs and YAP1RUNX3 binds TEADs and YAP1RUNX3 interacts with both YAP1 and TEAD proteins. The interaction with YAP1 involves the PY motif of RUNX3 and the WW domain of YAP1. The interaction with TEADs involves the Runt domain of RUNX3 and the DNA recognition helix of TEADs. RUNX3 was shown to directly interact with TEAD1 and TEAD4. Based on sequence similarity, it is highly probable that RUNX3 also interacts with TEAD2 and TEAD3. The interaction of RUNX3 with YAP1 and/or TEADs does not prevent formation of the YAP1:TEADs complex (Yagi et al. 1999, Qiao et al. 2015).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 89516781nucleoplasmGO0005654YAP1:TEAD1,TEAD4,(TEAD2,TEAD3) [nucleoplasm]YAP1:TEAD1,TEAD4,(TEAD2,TEAD3)Reactome DB_ID: 12533221UniProt:P46937 YAP1YAP1YAP1YAP65FUNCTION Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role to control cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750).SUBUNIT Binds to the SH3 domain of the YES kinase. Binds to WBP1 and WBP2 (PubMed:9202023). Binds, in vitro, through the WW1 domain, to neural isoforms of ENAH that contain the PPSY motif (By similarity). The phosphorylated form interacts with YWHAB (PubMed:17974916). Interacts (via WW domains) with LATS1 (via PPxY motif 2) (PubMed:18158288). Interacts with LATS2 (PubMed:18158288). Isoform 2 and isoform 3 interact (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2) (PubMed:12807903). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 (PubMed:18579750, PubMed:20123905, PubMed:20123908). Interacts with TP73 (PubMed:18280240). Interacts with RUNX1 (PubMed:18280240). Interacts with HCK (PubMed:17535448). Interacts (via WW domains) with PTPN14 (via PPxY motif 2); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional coactivator activity (PubMed:22525271).TISSUE SPECIFICITY Increased expression seen in some liver and prostate cancers. Isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level).DOMAIN The first coiled-coil region mediates most of the interaction with TEAD transcription factors.PTM Phosphorylated by LATS1 and LATS2; leading to cytoplasmic translocation and inactivation (PubMed:18158288, PubMed:20048001). Phosphorylated by ABL1; leading to YAP1 stabilization, enhanced interaction with TP73 and recruitment onto proapoptotic genes; in response to DNA damage (PubMed:18280240). Phosphorylation at Ser-400 and Ser-403 by CK1 is triggered by previous phosphorylation at Ser-397 by LATS proteins and leads to YAP1 ubiquitination by SCF(beta-TRCP) E3 ubiquitin ligase and subsequent degradation (PubMed:20048001). Phosphorylated at Thr-119, Ser-138, Thr-154, Ser-367 and Thr-412 by MAPK8/JNK1 and MAPK9/JNK2, which is required for the regulation of apoptosis by YAP1 (PubMed:21364637).PTM Ubiquitinated by SCF(beta-TRCP) E3 ubiquitin ligase.SIMILARITY Belongs to the YAP1 family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP46937Chain Coordinates1EQUAL504EQUALConverted from EntitySet in ReactomeReactome DB_ID: 89516771TEAD1,TEAD4,(TEAD2,TEAD3) [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTEAD4 [nucleoplasm]TEAD1 [nucleoplasm]UniProtQ15561UniProtP28347Reactome Database ID Release 758951678Database 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=8951678ReactomeR-HSA-89516781Reactome 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-8951678.1Reactome DB_ID: 88653931UniProt:Q13761 RUNX3RUNX3CBFA3PEBP2A3AML2RUNX3FUNCTION 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.UniProtQ137611EQUAL415EQUALReactome DB_ID: 89516791RUNX3:YAP1:TEAD1,TEAD4,(TEAD2,TEAD3) [nucleoplasm]RUNX3:YAP1:TEAD1,TEAD4,(TEAD2,TEAD3)Reactome DB_ID: 89516781Reactome DB_ID: 886539311EQUAL415EQUALReactome Database ID Release 758951679Database 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=8951679ReactomeR-HSA-89516791Reactome 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-8951679.1Reactome Database ID Release 758951676Database 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=8951676ReactomeR-HSA-89516763Reactome 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-8951676.326364597Pubmed2016RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancerQiao, YLin, S JChen, YVoon, D C-CZhu, FChuang, L S HWang, TTan, PLee, S CYeoh, K GSudol, MIto, YOncogene 35:2664-7410228168Pubmed1999A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activatorYagi, RChen, L FShigesada, KMurakami, YIto, YEMBO J. 18:2551-62TEADs:YAP1 binds CTGF geneTEADs:YAP1 binds CTGF geneThe complex of YAP1 and one TEAD proteins (TEAD1, TEAD2, TEAD3 or TEAD4) binds to TEAD-binding sites in the promoter of the CTGF gene (Zhao et al. 2008). Association of RUNX3 with the TEADs:YAP1 complex inhibits loading of the TEADs:YAP1 to the CTGF promoter (Qiao et al. 2016).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Converted from EntitySet in ReactomeReactome DB_ID: 88696391TEADs:YAP1 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 56499371ENSEMBL:ENSG00000118523 CTGFIGFBP8CCN2HCS24CTGFENSEMBLENSG00000118523Reactome DB_ID: 89516971TEADs:YAP1:CTGF gene [nucleoplasm]TEADs:YAP1:CTGF geneConverted from EntitySet in ReactomeReactome DB_ID: 88696391Reactome DB_ID: 56499371Reactome Database ID Release 758951697Database 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=8951697ReactomeR-HSA-89516971Reactome 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-8951697.1Reactome Database ID Release 758951695Database 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=8951695ReactomeR-HSA-89516954Reactome 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-8951695.418579750Pubmed2008TEAD mediates YAP-dependent gene induction and growth controlZhao, BYe, XinYu, JLi, LLi, WLi, SimingYu, JianjunLin, Jiandie DWang, Cun-YuChinnaiyan, Arul MLai, ZCGuan, KLGenes Dev. 22:1962-71INHIBITIONReactome Database ID Release 758951699Database 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=8951699ReactomeR-HSA-89516991Reactome 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-8951699.1Reactome DB_ID: 8951679Expression of CTGFExpression of CTGFThe CTGF gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of the CTGF gene is increased by both YAP1:TEAD and WWTR1(TAZ):TEAD transcriptional coactivator:transcription factor complexes, so that CTGF is one of the many genes whose expression is downregulated by the action of the hippo cascade (Zhang et al. 2009; Zhao et al. 2008).Authored: May, B, 2011-11-08Reviewed: Kersten, S, 2009-06-08Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: May, B, 2011-11-08Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 56499371Reactome DB_ID: 5611481extracellular regionGO0005576UniProt:P29279 CCN2CCN2IGFBP8CCN2HCS24CTGFFUNCTION Major connective tissue mitoattractant secreted by vascular endothelial cells. Promotes proliferation and differentiation of chondrocytes. Mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells. Enhances fibroblast growth factor-induced DNA synthesis.SUBUNIT Monomer.TISSUE SPECIFICITY Expressed in bone marrow and thymic cells. Also expressed one of two Wilms tumors tested.SIMILARITY Belongs to the CCN family.UniProtP2927927EQUAL349EQUALReactome Database ID Release 751989766Database 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=1989766ReactomeR-HSA-19897665Reactome 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-1989766.520110263Pubmed2010Profiling of promoter occupancy by PPAR{alpha} in human hepatoma cells via ChIP-chip analysisvan der Meer, DLDegenhardt, TVaisanen, Sde Groot, PJHeinaniemi, Mde Vries, SCMuller, MCarlberg, CKersten, SanderNucleic Acids Res19324877Pubmed2009TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transitionZhang, HLiu, CYZha, ZYZhao, BYao, JZhao, SXiong, YLei, QGuan, KLJ Biol Chem 284:13355-6219324876Pubmed2009TEADs mediate nuclear retention of TAZ to promote oncogenic transformationChan, SWLim, CJLoo, LSChong, YFHuang, CHong, WJ Biol Chem 284:14347-58ACTIVATIONReactome Database ID Release 752032788Database 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=2032788ReactomeR-HSA-20327882Reactome 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-2032788.2Converted from EntitySet in ReactomeReactome DB_ID: 8869639ACTIVATIONReactome Database ID Release 752032783Database 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=2032783ReactomeR-HSA-20327831Reactome 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-2032783.1Reactome DB_ID: 2032762TEAD:WWTR1(TAZ) [nucleoplasm]TEAD:WWTR1(TAZ)Reactome DB_ID: 16297751UniProt:Q9GZV5 WWTR1WWTR1WWTR1TAZFUNCTION Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.SUBUNIT Binds to SLC9A3R2 via the PDZ motif at the plasma membrane. Binds to YWHAZ in vivo and in vitro through the phosphoserine-binding motif RSHSSP (By similarity). Interacts (via coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4. Interacts with MED15, PAX8 and NKX2-1. Interacts with TEAD1, TEAD2, TEAD3 and TEAD4.TISSUE SPECIFICITY Highly expressed in kidney, heart, placenta and lung. Expressed in the thyroid tissue.DOMAIN The PDZ-binding motif is essential for stimulated gene transcription. It localizes the protein into both punctate nuclear foci and plasma membrane-associated complexes (By similarity).DOMAIN Binds to transcription factors via its WW domain.PTM Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2 results in creation of 14-3-3 binding sites, retention in the cytoplasm, and functional inactivation. Phosphorylation results in the inhibition of transcriptional coactivation through YWHAZ-mediated nuclear export.UniProtQ9GZV51EQUAL400EQUALConverted from EntitySet in ReactomeReactome DB_ID: 20327731TEADs [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTEAD2 [nucleoplasm]TEAD4 [nucleoplasm]TEAD1 [nucleoplasm]TEAD3 [nucleoplasm]UniProtQ15562UniProtQ99594Reactome Database ID Release 752032762Database 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=2032762ReactomeR-HSA-20327625Reactome 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-2032762.5Reactome Database ID Release 758951671Database 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=8951671ReactomeR-HSA-89516711Reactome 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-8951671.1