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

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33, 554, 544, 8, 11, 5432, 47, 55, 585416, 2954555454cytosolnucleoplasmTEAD2WWTR1 CTGFTEAD2 WWTR1 TEAD4 TEAD2 TEAD4 TEAD3 TBX5:WWTR1:PCAFTEAD2 TEAD3YAP1 NKX2-5:GATA4:HIPK1,2RUNX2-P2 TEAD2:YAP1RUNX2RUNX2-P1 TEAD1 Transcriptionalregulation by RUNX2WWTR1TBX5 TEAD3 TEAD3 HIPK1 NPPA(1-153)RUNX2:WWTR1(TAZ)RUNX2-P1 YAP1 TBX5YAP1 TEAD:WWTR1(TAZ)TEAD1 NPPA geneTEAD4 TEAD3 TEADs:YAP1TEAD1:YAP1YAP1 TEAD1 YAP1KAT2BTEAD4:YAP1WWTR1 HIPK2 TEAD1KAT2B GATA4 TEAD4TEAD1 NKX2-5 Signaling by HippoRUNX2-P2 TEAD2 TEAD4 YAP1 TEADsCTGF geneTEAD3:YAP1556, 12, 17, 18, 24...1-3, 5, 7...4, 54


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: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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  34. Sudol M, Harvey KF.; ''Modularity in the Hippo signaling pathway.''; PubMed Europe PMC
  35. 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
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  37. 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
  38. 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
  39. 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
  40. Ito Y, Bae SC, Chuang LS.; ''The RUNX family: developmental regulators in cancer.''; PubMed Europe PMC
  41. Le Marer N.; ''GALECTIN-3 expression in differentiating human myeloid cells.''; PubMed Europe PMC
  42. Ducy P, Karsenty G.; ''Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene.''; PubMed Europe PMC
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  45. 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
  46. Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P.; ''Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.''; PubMed Europe PMC
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  48. Tandon M, Chen Z, Pratap J.; ''Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells.''; PubMed Europe PMC
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  51. 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
  52. Otto F, Kanegane H, Mundlos S.; ''Mutations in the RUNX2 gene in patients with cleidocranial dysplasia.''; PubMed Europe PMC
  53. 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
  54. 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
  55. 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
  56. 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
  57. 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
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  59. 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


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87190view08:26, 19 July 2016EgonwOntology Term : 'regulatory pathway' added !
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76971view08:26, 17 July 2014ReactomeTeamFixed remaining interactions
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75710view11:05, 10 June 2014ReactomeTeamReactome 48 Update
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External references


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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

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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)
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