YAP1- and WWTR1 (TAZ)-stimulated gene expression (Homo sapiens)

From WikiPathways

Jump to: navigation, search
29, 43454527, 33, 43, 514, 17436, 45455, 6, 15, 4545nucleoplasmcytosolWWTR1 TEAD4YAP1 RUNX2:WWTR1(TAZ)CTGFTEAD3 TEAD3 NPPA geneTEAD2TEAD3RUNX2YAP1TBX5TEAD1 Transcriptionalregulation by RUNX2TEAD4 TEAD:WWTR1(TAZ)TEAD3 YAP1 TEAD4:YAP1NPPA(1-153)HIPK2 TEAD4 RUNX2-P1 TEAD1 TEAD2 TEADs:YAP1TEAD2 RUNX2-P2 YAP1 WWTR1TEAD2:YAP1TEAD2 WWTR1 TEAD1 TEAD3:YAP1NKX2-5 TEAD1:YAP1RUNX2-P2 HIPK1 TEAD4 TEAD3 GATA4 TEAD2 TEAD4 KAT2BTBX5 KAT2B TEADsRUNX2-P1 NKX2-5:GATA4:HIPK1,2TEAD1YAP1 TBX5:WWTR1:PCAFYAP1 Signaling by HippoCTGF geneTEAD1 WWTR1 1-3, 8-14, 18...6, 457, 16, 25, 29-31, 39...43


YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010). View original pathway at Reactome.


Pathway is converted from Reactome ID: 2032785
Reactome version: 75
Reactome Author 
Reactome Author: D'Eustachio, Peter

Quality Tags

Ontology Terms



View all...
  1. Karsenty G.; ''Transcriptional control of skeletogenesis.''; PubMed Europe PMC Scholia
  2. Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G.; ''Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice.''; PubMed Europe PMC Scholia
  3. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G.; ''Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.''; PubMed Europe PMC Scholia
  4. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB.; ''TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.''; PubMed Europe PMC Scholia
  5. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL.; ''TEAD mediates YAP-dependent gene induction and growth control.''; PubMed Europe PMC Scholia
  6. Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL.; ''TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition.''; PubMed Europe PMC Scholia
  7. Zhao B, Li L, Lei Q, Guan KL.; ''The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version.''; PubMed Europe PMC Scholia
  8. Li XQ, Du X, Li DM, Kong PZ, Sun Y, Liu PF, Wang QS, Feng YM.; ''ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway.''; PubMed Europe PMC Scholia
  9. Zhang HY, Jin L, Stilling GA, Ruebel KH, Coonse K, Tanizaki Y, Raz A, Lloyd RV.; ''RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors.''; PubMed Europe PMC Scholia
  10. Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW.; ''The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation.''; PubMed Europe PMC Scholia
  11. Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH.; ''Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice.''; PubMed Europe PMC Scholia
  12. Tandon M, Chen Z, Pratap J.; ''Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells.''; PubMed Europe PMC Scholia
  13. Lee MH, Kim YJ, Yoon WJ, Kim JI, Kim BG, Hwang YS, Wozney JM, Chi XZ, Bae SC, Choi KY, Cho JY, Choi JY, Ryoo HM.; ''Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter.''; PubMed Europe PMC Scholia
  14. Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, Satake M, Takada K, Komori T.; ''Core-binding factor beta interacts with Runx2 and is required for skeletal development.''; PubMed Europe PMC Scholia
  15. van der Meer DL, Degenhardt T, Väisänen S, de Groot PJ, Heinäniemi M, de Vries SC, Müller M, Carlberg C, Kersten S.; ''Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.''; PubMed Europe PMC Scholia
  16. Sudol M, Harvey KF.; ''Modularity in the Hippo signaling pathway.''; PubMed Europe PMC Scholia
  17. Cui CB, Cooper LF, Yang X, Karsenty G, Aukhil I.; ''Transcriptional coactivation of bone-specific transcription factor Cbfa1 by TAZ.''; PubMed Europe PMC Scholia
  18. Roca H, Phimphilai M, Gopalakrishnan R, Xiao G, Franceschi RT.; ''Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene.''; PubMed Europe PMC Scholia
  19. Yang DC, Yang MH, Tsai CC, Huang TF, Chen YH, Hung SC.; ''Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST.''; PubMed Europe PMC Scholia
  20. Vladimirova V, Waha A, Lückerath K, Pesheva P, Probstmeier R.; ''Runx2 is expressed in human glioma cells and mediates the expression of galectin-3.''; PubMed Europe PMC Scholia
  21. Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T.; ''Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog.''; PubMed Europe PMC Scholia
  22. Zhang YY, Li X, Qian SW, Guo L, Huang HY, He Q, Liu Y, Ma CG, Tang QQ.; ''Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis.''; PubMed Europe PMC Scholia
  23. Robledo RF, Rajan L, Li X, Lufkin T.; ''The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development.''; PubMed Europe PMC Scholia
  24. Sato M, Morii E, Komori T, Kawahata H, Sugimoto M, Terai K, Shimizu H, Yasui T, Ogihara H, Yasui N, Ochi T, Kitamura Y, Ito Y, Nomura S.; ''Transcriptional regulation of osteopontin gene in vivo by PEBP2alphaA/CBFA1 and ETS1 in the skeletal tissues.''; PubMed Europe PMC Scholia
  25. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W.; ''Hippo pathway-independent restriction of TAZ and YAP by angiomotin.''; PubMed Europe PMC Scholia
  26. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G.; ''A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.''; PubMed Europe PMC Scholia
  27. Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S.; ''The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression.''; PubMed Europe PMC Scholia
  28. Drissi H, Luc Q, Shakoori R, Chuva De Sousa Lopes S, Choi JY, Terry A, Hu M, Jones S, Neil JC, Lian JB, Stein JL, Van Wijnen AJ, Stein GS.; ''Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene.''; PubMed Europe PMC Scholia
  29. Oh H, Irvine KD.; ''Yorkie: the final destination of Hippo signaling.''; PubMed Europe PMC Scholia
  30. Xiao L, Chen Y, Ji M, Dong J.; ''KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.''; PubMed Europe PMC Scholia
  31. Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S.; ''MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation.''; PubMed Europe PMC Scholia
  32. Long F.; ''Building strong bones: molecular regulation of the osteoblast lineage.''; PubMed Europe PMC Scholia
  33. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD.; ''Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.''; PubMed Europe PMC Scholia
  34. Wysokinski D, Blasiak J, Pawlowska E.; ''Role of RUNX2 in Breast Carcinogenesis.''; PubMed Europe PMC Scholia
  35. Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP.; ''Cbfbeta interacts with Runx2 and has a critical role in bone development.''; PubMed Europe PMC Scholia
  36. Tribioli C, Lufkin T.; ''The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen.''; PubMed Europe PMC Scholia
  37. Mortus JR, Zhang Y, Hughes DP.; ''Developmental pathways hijacked by osteosarcoma.''; PubMed Europe PMC Scholia
  38. Lengner CJ, Hassan MQ, Serra RW, Lepper C, van Wijnen AJ, Stein JL, Lian JB, Stein GS.; ''Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation.''; PubMed Europe PMC Scholia
  39. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J.; ''TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner.''; PubMed Europe PMC Scholia
  40. Underwood KF, D'Souza DR, Mochin-Peters M, Pierce AD, Kommineni S, Choe M, Bennett J, Gnatt A, Habtemariam B, MacKerell AD, Passaniti A.; ''Regulation of RUNX2 transcription factor-DNA interactions and cell proliferation by vitamin D3 (cholecalciferol) prohormone activity.''; PubMed Europe PMC Scholia
  41. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL, Attisano L.; ''The Hippo pathway regulates Wnt/beta-catenin signaling.''; PubMed Europe PMC Scholia
  42. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G.; ''A twist code determines the onset of osteoblast differentiation.''; PubMed Europe PMC Scholia
  43. Murakami M, Nakagawa M, Olson EN, Nakagawa O.; ''A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.''; PubMed Europe PMC Scholia
  44. Le Marer N.; ''GALECTIN-3 expression in differentiating human myeloid cells.''; PubMed Europe PMC Scholia
  45. Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W.; ''TEADs mediate nuclear retention of TAZ to promote oncogenic transformation.''; PubMed Europe PMC Scholia
  46. Teplyuk NM, Galindo M, Teplyuk VI, Pratap J, Young DW, Lapointe D, Javed A, Stein JL, Lian JB, Stein GS, van Wijnen AJ.; ''Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors.''; PubMed Europe PMC Scholia
  47. Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M.; ''Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling.''; PubMed Europe PMC Scholia
  48. Otto F, Kanegane H, Mundlos S.; ''Mutations in the RUNX2 gene in patients with cleidocranial dysplasia.''; PubMed Europe PMC Scholia
  49. Karsenty G, Olson EN.; ''Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication.''; PubMed Europe PMC Scholia
  50. Ito Y, Bae SC, Chuang LS.; ''The RUNX family: developmental regulators in cancer.''; PubMed Europe PMC Scholia
  51. Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG.; ''Congenital heart disease caused by mutations in the transcription factor NKX2-5.''; PubMed Europe PMC Scholia
  52. Pan D.; ''The hippo signaling pathway in development and cancer.''; PubMed Europe PMC Scholia
  53. Pierce AD, Anglin IE, Vitolo MI, Mochin MT, Underwood KF, Goldblum SE, Kommineni S, Passaniti A.; ''Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype.''; PubMed Europe PMC Scholia
  54. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B.; ''Dominance of SOX9 function over RUNX2 during skeletogenesis.''; PubMed Europe PMC Scholia
  55. Ducy P, Karsenty G.; ''Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene.''; PubMed Europe PMC Scholia
  56. Li XQ, Lu JT, Tan CC, Wang QS, Feng YM.; ''RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization.''; PubMed Europe PMC Scholia
  57. Pande S, Browne G, Padmanabhan S, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS.; ''Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.''; PubMed Europe PMC Scholia
  58. Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P.; ''Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.''; PubMed Europe PMC Scholia
  59. Kammerer M, Gutzwiller S, Stauffer D, Delhon I, Seltenmeyer Y, Fournier B.; ''Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform.''; PubMed Europe PMC Scholia


View all...
114969view16:49, 25 January 2021ReactomeTeamReactome version 75
113413view11:48, 2 November 2020ReactomeTeamReactome version 74
112615view15:59, 9 October 2020ReactomeTeamReactome version 73
101531view11:40, 1 November 2018ReactomeTeamreactome version 66
101066view21:22, 31 October 2018ReactomeTeamreactome version 65
100596view19:56, 31 October 2018ReactomeTeamreactome version 64
100145view16:41, 31 October 2018ReactomeTeamreactome version 63
99695view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99283view12:46, 31 October 2018ReactomeTeamreactome version 62
93910view13:44, 16 August 2017ReactomeTeamreactome version 61
93486view11:24, 9 August 2017ReactomeTeamreactome version 61
87190view08:26, 19 July 2016EgonwOntology Term : 'regulatory pathway' added !
86582view09:21, 11 July 2016ReactomeTeamreactome version 56
83145view10:09, 18 November 2015ReactomeTeamVersion54
81495view13:02, 21 August 2015ReactomeTeamVersion53
76971view08:26, 17 July 2014ReactomeTeamFixed remaining interactions
76676view12:04, 16 July 2014ReactomeTeamFixed remaining interactions
76004view10:06, 11 June 2014ReactomeTeamRe-fixing comment source
75710view11:05, 10 June 2014ReactomeTeamReactome 48 Update
75064view13:57, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74708view08:47, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
CTGF geneGeneProductENSG00000118523 (Ensembl)
CTGFProteinP29279 (Uniprot-TrEMBL)
GATA4 ProteinP43694 (Uniprot-TrEMBL)
HIPK1 ProteinQ86Z02 (Uniprot-TrEMBL)
HIPK2 ProteinQ9H2X6 (Uniprot-TrEMBL)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
KAT2BProteinQ92831 (Uniprot-TrEMBL)
NKX2-5 ProteinP52952 (Uniprot-TrEMBL)
NKX2-5:GATA4:HIPK1,2ComplexR-HSA-5578875 (Reactome)
NPPA geneGeneProductENSG00000175206 (Ensembl)
NPPA(1-153)ProteinP01160 (Uniprot-TrEMBL)
RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
RUNX2:WWTR1(TAZ)ComplexR-HSA-2064919 (Reactome)
RUNX2ComplexR-HSA-9007751 (Reactome)
Signaling by HippoPathwayR-HSA-2028269 (Reactome) Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).

There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).

In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.

Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).

In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.

Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010).

TBX5 ProteinQ99593 (Uniprot-TrEMBL)
TBX5:WWTR1:PCAFComplexR-HSA-2032799 (Reactome)
TBX5ProteinQ99593 (Uniprot-TrEMBL)
TEAD1 ProteinP28347 (Uniprot-TrEMBL)
TEAD1:YAP1ComplexR-HSA-8869643 (Reactome)
TEAD1ProteinP28347 (Uniprot-TrEMBL)
TEAD2 ProteinQ15562 (Uniprot-TrEMBL)
TEAD2:YAP1ComplexR-HSA-8869640 (Reactome)
TEAD2ProteinQ15562 (Uniprot-TrEMBL)
TEAD3 ProteinQ99594 (Uniprot-TrEMBL)
TEAD3:YAP1ComplexR-HSA-8869638 (Reactome)
TEAD3ProteinQ99594 (Uniprot-TrEMBL)
TEAD4 ProteinQ15561 (Uniprot-TrEMBL)
TEAD4:YAP1ComplexR-HSA-8869641 (Reactome)
TEAD4ProteinQ15561 (Uniprot-TrEMBL)
TEAD:WWTR1(TAZ)ComplexR-HSA-2032762 (Reactome)
TEADs:YAP1ComplexR-HSA-8869639 (Reactome)
TEADsComplexR-HSA-2032773 (Reactome)
Transcriptional regulation by RUNX2PathwayR-HSA-8878166 (Reactome) RUNX2 (CBFA1 or AML3) transcription factor, similar to other RUNX family members, RUNX1 and RUNX3, can function in complex with CBFB (CBF-beta) (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002). RUNX2 mainly regulates transcription of genes involved in skeletal development (reviewed in Karsenty 2008). RUNX2 is involved in development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. RUNX2 stimulates transcription of the BGLAP gene (Ducy and Karsenty 1995, Ducy et al. 1997), which encodes Osteocalcin, a bone-derived hormone which is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). RUNX2 directly controls the expression of most genes associated with osteoblast differentiation and function (Sato et al. 1998, Ducy et al. 1999, Roce et al. 2005). RUNX2-mediated transcriptional regulation of several genes involved in GPCR (G protein coupled receptor) signaling is implicated in the control of growth of osteoblast progenitors (Teplyuk et al. 2009). RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004). Germline loss-of-function mutations of the RUNX2 gene are associated with cleidocranial dysplasia syndrome (CCD), an autosomal skeletal disorder (reviewed in Jaruga et al. 2016). The function of RUNX2 is frequently disrupted in osteosarcoma (reviewed in Mortus et al. 2014). Vitamin D3 is implicated in regulation of transcriptional activity of the RUNX2:CBFB complex (Underwood et al. 2012).

RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).

RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).

RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).

For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015.

WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1ProteinP46937 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
CTGF geneR-HSA-1989766 (Reactome)
CTGFArrowR-HSA-1989766 (Reactome)
KAT2BR-HSA-2032794 (Reactome)
NKX2-5:GATA4:HIPK1,2ArrowR-HSA-2032800 (Reactome)
NPPA geneR-HSA-2032800 (Reactome)
NPPA(1-153)ArrowR-HSA-2032800 (Reactome)
R-HSA-1989766 (Reactome) The 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).
R-HSA-2032775 (Reactome) In the nucleus the YAP1 transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009).
R-HSA-2032781 (Reactome) In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009; Zhang et al. 2009).
R-HSA-2032794 (Reactome) In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the TBX5 transcription factor and PCAF (KAT2B) histone acetyltransferase to form a complex. The stoichiometry of this complex is unknown (Murakami et al. 2005).
R-HSA-2032800 (Reactome) Transcription of the NPPA (ANF) gene is stimulated by the action of a transcription factor complex that includes WWTR1 (TAZ), TBX5, and the PCAF (KAT2B) histone acetyltransferase (Murakami et al. 2005). Homeobox protein NKX-2.5 (NKX2-5), in cooperation with transcription factor GATA-4 (GATA4) and interacting partners homeodomain-interacting protein kinase 1 and 2 (HIPK1 and 2), acts as a transcriptional activator factor of NPPA in mice (Lee et al. 1998). Defects in NKX2-5 can cause diverse cardiac developmental disorders (Schott et al. 1998, Benson et al. 1999).
R-HSA-2064932 (Reactome) In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the RUNX2 transcription factor to form a complex. This interaction has not been experimentally characterized in human cells but is inferred from properties of the homologous mouse proteins. The stoichiometry of this complex is unknown (Cui et al. 2003).

Formation of the RUNX2:WWTR1 complex is implicated in promotion of luminal breast cancer progression through regulation of E-cadherin (CDH1) and cross-talk with ERBB2 (HER2) signaling (Brusgard et al. 2015).

R-HSA-8871260 (Reactome) The YAP1 transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009).
R-HSA-8871265 (Reactome) The YAP1 transcriptional coactivator can bind any one of the four TEAD family transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009).
R-HSA-8871266 (Reactome) YAP1 is a transcriptional coactivator that can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009).
RUNX2:WWTR1(TAZ)ArrowR-HSA-2064932 (Reactome)
RUNX2R-HSA-2064932 (Reactome)
TBX5:WWTR1:PCAFArrowR-HSA-2032794 (Reactome)
TBX5:WWTR1:PCAFArrowR-HSA-2032800 (Reactome)
TBX5R-HSA-2032794 (Reactome)
TEAD1:YAP1ArrowR-HSA-2032775 (Reactome)
TEAD1R-HSA-2032775 (Reactome)
TEAD2:YAP1ArrowR-HSA-8871260 (Reactome)
TEAD2R-HSA-8871260 (Reactome)
TEAD3:YAP1ArrowR-HSA-8871266 (Reactome)
TEAD3R-HSA-8871266 (Reactome)
TEAD4:YAP1ArrowR-HSA-8871265 (Reactome)
TEAD4R-HSA-8871265 (Reactome)
TEAD:WWTR1(TAZ)ArrowR-HSA-1989766 (Reactome)
TEAD:WWTR1(TAZ)ArrowR-HSA-2032781 (Reactome)
TEADs:YAP1ArrowR-HSA-1989766 (Reactome)
TEADsR-HSA-2032781 (Reactome)
WWTR1R-HSA-2032781 (Reactome)
WWTR1R-HSA-2032794 (Reactome)
WWTR1R-HSA-2064932 (Reactome)
YAP1R-HSA-2032775 (Reactome)
YAP1R-HSA-8871260 (Reactome)
YAP1R-HSA-8871265 (Reactome)
YAP1R-HSA-8871266 (Reactome)
Personal tools