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

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4, 81, 3, 5, 82, 7, 92, 9826cytosolnucleoplasmTEAD2 Palm TEAD4 TEAD:YAP1NCOA2 WWTR1 TEAD3 TEAD1 LINA ALA TBL1XR1 MED1 TEAD2 YAP1 TEAD3 NCOA1 RUNX2:WWTR1(TAZ)TEAD:WWTR1(TAZ)CHD9 AA RUNX2EPA YAP1TEAD4 CARM1 SMARCD3 RXRA TBX5WWTR1 CTGFTEADNCOA6 TBX5 TGS1 CREBBP PPARA:RXRACoactivator complexTEAD1 KAT2BHELZ2 WWTR1RUNX2 KAT2B NPPA(1-153)WWTR1 TBL1X PPARA TBX5:WWTR1:PCAF82, 92


Description

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). Source:Reactome.

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Bibliography

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  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

History

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CompareRevisionActionTimeUserComment
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

DataNodes

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NameTypeDatabase referenceComment
AA MetaboliteCHEBI:15843 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CTGFProteinP29279 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
KAT2BProteinQ92831 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
MED1 ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
NCOA1 ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 ProteinQ15596 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NPPA(1-153)ProteinP01160 (Uniprot-TrEMBL)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
Palm MetaboliteCHEBI:15756 (ChEBI)
RUNX2 ProteinQ13950 (Uniprot-TrEMBL)
RUNX2:WWTR1(TAZ)ComplexR-HSA-2064919 (Reactome)
RUNX2ProteinQ13950 (Uniprot-TrEMBL)
RXRA ProteinP19793 (Uniprot-TrEMBL)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TBX5 ProteinQ99593 (Uniprot-TrEMBL)
TBX5:WWTR1:PCAFComplexR-HSA-2032799 (Reactome)
TBX5ProteinQ99593 (Uniprot-TrEMBL)
TEAD1 ProteinP28347 (Uniprot-TrEMBL)
TEAD2 ProteinQ15562 (Uniprot-TrEMBL)
TEAD3 ProteinQ99594 (Uniprot-TrEMBL)
TEAD4 ProteinQ15561 (Uniprot-TrEMBL)
TEAD:WWTR1(TAZ)ComplexR-HSA-2032762 (Reactome)
TEAD:YAP1ComplexR-HSA-2032772 (Reactome)
TEADProteinR-HSA-2032773 (Reactome)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1ProteinP46937 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CTGFArrowR-HSA-1989766 (Reactome)
KAT2BR-HSA-2032794 (Reactome)
NPPA(1-153)ArrowR-HSA-2032800 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-1989766 (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 CTFG 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).
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)
TEAD:WWTR1(TAZ)ArrowR-HSA-1989766 (Reactome)
TEAD:WWTR1(TAZ)ArrowR-HSA-2032781 (Reactome)
TEAD:YAP1ArrowR-HSA-1989766 (Reactome)
TEAD:YAP1ArrowR-HSA-2032775 (Reactome)
TEADR-HSA-2032775 (Reactome)
TEADR-HSA-2032781 (Reactome)
WWTR1R-HSA-2032781 (Reactome)
WWTR1R-HSA-2032794 (Reactome)
WWTR1R-HSA-2064932 (Reactome)
YAP1R-HSA-2032775 (Reactome)
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