YAP1

Yes-associated protein 1
PDB rendering based on 1jmq.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1JMQ​, 1K5R​, 1K9Q​, 1K9R​, 2LAW​, 2LAX​, 2LAY​, 2LTV​, 2LTW​, 3KYS​, 3MHR​, 4RE1​
Identifiers
Symbols	YAP1 ; COB1; YAP; YAP2; YAP65; YKI
External IDs	OMIM: 606608 MGI: 103262 HomoloGene: 4452 GeneCards: YAP1 Gene
Gene ontology Molecular function • RNA polymerase II core promoter sequence-specific DNA binding • transcription factor activity, RNA polymerase II transcription factor binding • chromatin binding • transcription coactivator activity • transcription corepressor activity • protein binding • protein C-terminus binding • transcription regulatory region DNA binding • proline-rich region binding Cellular component • nucleus • nucleoplasm • transcription factor complex • cytoplasm • cytosol • membrane • cell junction Biological process • cell morphogenesis • vasculogenesis • embryonic heart tube morphogenesis • transcription initiation from RNA polymerase II promoter • cellular response to DNA damage stimulus • cell proliferation • positive regulation of cell proliferation • gene expression • regulation of keratinocyte proliferation • keratinocyte differentiation • negative regulation of epithelial cell differentiation • notochord development • somatic stem cell maintenance • hippo signaling • positive regulation of transcription from RNA polymerase II promoter • positive regulation of organ growth • paraxial mesoderm development • lateral mesoderm development • regulation of neurogenesis • contact inhibition • bud elongation involved in lung branching • lung epithelial cell differentiation • cellular response to retinoic acid • cellular response to gamma radiation • regulation of stem cell proliferation • regulation of metanephric nephron tubule epithelial cell differentiation • positive regulation of canonical Wnt signaling pathway • positive regulation of stem cell maintenance • negative regulation of nucleic acid-templated transcription • negative regulation of stem cell differentiation • negative regulation of extrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10413	22601
Ensembl	ENSG00000137693	ENSMUSG00000053110
UniProt	P46937	P46938
RefSeq (mRNA)	NM_001130145	NM_001171147
RefSeq (protein)	NP_001123617	NP_001164618
Location (UCSC)	Chr 11: 102.11 – 102.23 Mb	Chr 9: 7.93 – 8 Mb
PubMed search

YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. YAP1 is inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases.^[1] YAP1 is a potent oncogene, which is amplified in various human cancers.^[2][3]

Structure

Modular Structure of YAP1 Isoforms

Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain.^[4][5][6] Two splice isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids that encoded the WW domain.^[7][8] Apart from the WW domain, the modular structure of YAP1 contains a proline-rich region at the very amino terminus, which is followed by a TID (TEAD transcription factor interacting domain).^[9] Next, following a single WW domain, which is present in the YAP1-1 isoform, and two WW domains, which are present in the YAP1-2 isoform, there is the SH3-BM (Src Homology 3 binding motif).^[1][10] Following the SH3-BM is a TAD (transcription activation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1).^[11][12]

Function

YAP1 is a transcriptional co-activator^[13] and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors,^[9] which up-regulate genes that promote cell growth and inhibit apoptosis.^[14] Several other functional partners of YAP1 were identified, including RUNX,^[13] SMADs,^[15][16] p73,^[17] ErbB4,^[18][19] TP53BP,^[20] LATS1/2,^[21] PTPN14,^[22] AMOTs,^{[23][24][25][26]} and ZO1/2.^[27] YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway.^[28] When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins.^[28] When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression.^[28]

It is reported that several genes are regulated by YAP1, including Birc2, Birc5, connective tissue growth factor (CTGF), amphiregulin (AREG), Cyr61, Hoxa1 and Hoxc13.

YAP/TAZ have also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signalling cascade.^[29]

Clinical significance

Heterozygous loss-of-function mutations in the YAP1 gene have been identified in two families with major eye malformations with or without extra-ocular features such as hearing loss, cleft lip, intellectual disability and renal disease.^[30]

The YAP1 oncogene serves as a target for the development of new cancer drugs.^[31] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains.^[32][33] These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

References

1. Sudol M (1994). "Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product". Oncogene 9 (8): 2145–2152. PMID 8035999.
2. Huang, J., Wu, S., Barrera, J., Matthews, K., Pan, D. (2005). "The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP". Cell 122 (3): 421–34. doi:10.1016/j.cell.2005.06.007. PMID 16096061.
3. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. (2006). "Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon". Proc Natl Acad Sci U S A. 103 (33): 12405–12410. Bibcode:2006PNAS..10312405O. doi:10.1073/pnas.0605579103. PMC 1533802. PMID 16894141.
4. Bork, P., Sudol, M. (1994). "The WW domain: a signalling site in dystrophin". Trends in Biochem Sci 19 (12): 531–533. doi:10.1016/0968-0004(94)90053-1. PMID 7846762.
5. Andre, B., Springael, J.Y. (1994). "WWP, a new amino acid motif present in single or multiple copies in various proteins including dystrophin and the SH3-binding Yes-associated protein YAP65". Biochem Biophys Res Commun 205 (2): 1201–1205. doi:10.1006/bbrc.1994.2793. PMID 7802651.
6. Hofmann, K., Bucher, P. (1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Lett 358 (2): 153–157. doi:10.1016/0014-5793(94)01415-W. PMID 7828727.
7. Sudol, M., Bork, P., Einbond, A., Kastury, K., Druck, T., Negrini, M., Huebner, K., Lehman, D. (1995). "Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain". J Biol Chem 270 (24): 14733–14741. doi:10.1074/jbc.270.24.14733. PMID 7782338.
8. Gaffney, C.J., Oka, T., Mazack, V., Hilman, D., Gat, U., Muramatsu, T., Inazawa, J., Golden, A., Carey, D.J., Farooq, A., Tromp, G., Sudol, M. (2012). "Identification, Basic Characterization and Evolutionary Analysis of Differentially Spliced mRNA Isoforms of Human YAP1 Gene". Gene 509 (2): 215–222. doi:10.1016/j.gene.2012.08.025. PMC 3455135. PMID 22939869.
9. Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML (2001). "TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm". Genes Dev 15 (10): 1229–1241. doi:10.1101/gad.888601. PMC 313800. PMID 11358867.
10. Ren R, Mayer BJ, Cicchetti P, Baltimore D (1993). "Identification of a ten amino acid proline-rich SH3 binding site". Science 259 (5098): 1157–1161. doi:10.1126/science.8438166. PMID 8438166.
11. Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Lett 427 (1): 103–108. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608.
12. Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, et al. (1999). "Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50". J Cell Biol 147 (4): 879–890. doi:10.1083/jcb.147.4.879. PMC 2156157. PMID 10562288.
13. Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y (1999). "A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator". EMBO J 18 (9): 2551–2562. doi:10.1093/emboj/18.9.2551. PMC 1171336. PMID 10228168.
14. Zhao B, Kim J, Ye X, Lai ZC, Guan KL (2009). "Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein". Cancer Res 69 (3): 1089–98. doi:10.1158/0008-5472.CAN-08-2997. PMID 19141641.
15. Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, et al. (2002). "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling". Oncogene 21 (32): 4879–4884. doi:10.1038/sj.onc.1205623. PMID 12118366.
16. Aragón, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massagué, J., Macias, M.J. (2012). "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure 20 (10): 1726–36. doi:10.1016/j.str.2012.07.014. PMC 3472128. PMID 22921829.
17. Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, et al. (2001). "Physical interaction with Yes-associated protein enhances p73 transcriptional activity". J Biol Chem 276 (18): 15164–15173. doi:10.1074/jbc.M010484200. PMID 11278685.
18. Komuro A, Nagai M, Navin NE, Sudol M (2003). "WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus". J Biol Chem 278 (35): 33334–33341. doi:10.1074/jbc.M305597200. PMID 12807903.
19. Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M. (2004). "Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level". Exp Cell Res. 294 (2): 469–79. doi:10.1016/j.yexcr.2003.12.002. PMID 15023535.
20. Espanel X, Sudol M (2001). "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains". J Biol Chem 276 (17): 14514–14523. doi:10.1074/jbc.M008568200. PMID 11278422.
21. Oka T, Mazack V, and Sudol M (2008). "Mst2 and Lats kinases regulate apoptotic function of YAP". J Biol Chem 283 (41): 27534–27546. doi:10.1074/jbc.M804380200. PMID 18640976.
22. Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, et al. (2013). "PTPN14 interacts with and negatively regulates the oncogenic function of YAP". Oncogene 32 (10): 1266–1273. doi:10.1038/onc.2012.147. PMID 22525271.
23. Wang W, Huang J, Chen J (2011). "Angiomotin-like proteins associate with and negatively regulate YAP1". J Biol Chem 286 (6): 4364–4370. doi:10.1074/jbc.C110.205401. PMC 3039387. PMID 21187284.
24. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, et al. (2011). "Hippo pathway-independent restriction of TAZ and YAP by angiomotin". J Biol Chem 286 (9): 7018–7026. doi:10.1074/jbc.C110.212621. PMC 3044958. PMID 21224387.
25. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL (2011). "Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein". Genes Dev 25 (1): 51–63. doi:10.1101/gad.2000111. PMC 3012936. PMID 21205866.
26. Oka T, Schmitt AP, Sudol M (2012). "Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP". Oncogene 31 (1): 128–134. doi:10.1038/onc.2011.216. PMID 21685940.
27. Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu S, Vandekerckhove J, Gettemans J, Sudol M (2010). "Functional complex between YAP2 and ZO-2 is PDZ domain dependent, regulates YAP2 nuclear localization and signaling". Biochemical J 432 (3): 461–72. doi:10.1042/BJ20100870.
28. Pan D (2010). "The hippo signaling pathway in development and cancer". Dev Cell 19 (4): 491–505. doi:10.1016/j.devcel.2010.09.011. PMC 3124840. PMID 20951342.
29. McMurray, Rebecca J.; Dalby, Matthew J.; Tsimbouri, P. Monica (May 2015). "Using biomaterials to study stem cell mechanotransduction, growth and differentiation". Journal of Tissue Engineering and Regenerative Medicine 9 (5): 528–539. doi:10.1002/term.1957.
30. Williamson, KA; Rainger, J; Floyd, JA; Ansari, M; Meynert, A; Aldridge, KV; Rainger, JK; Anderson, CA; Moore, AT; Hurles, ME; Clarke, A; van Heyningen, V; Verloes, A; Taylor, MS; Wilkie, AO; UK10K, Consortium; Fitzpatrick, DR (Feb 6, 2014). "Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects.". American Journal of Human Genetics 94 (2): 295–302. doi:10.1016/j.ajhg.2014.01.001. PMID 24462371.
31. Sudol, M., Shields, D., Farooq, A. (2012). "Structures of YAP Protein Domains Reveal Promising Targets for Development of New Cancer Drugs". Seminars in Cell & Dev Biol 23 (7): 827–833. doi:10.1016/j.semcdb.2012.05.002. PMC 3427467. PMID 22609812.
32. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, et al. (2012). "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP". Genes Dev 26 (12): 1300–1305. doi:10.1101/gad.192856.112. PMC 3387657. PMID 22677547.
33. Kang, S.G., Huynh, T., Zhou, R. (2012). "Non-destructive Inhibition of Metallofullerenol Gd@(82)()H)(22) on WW domain: Implication for Signal Transduction Pathway". Sci Rep 2: 957, 1–7. doi:10.1038/srep00957. PMC 3518810. PMID 23233876.