YAP1

YAP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1JMQ, 1K5R, 1K9Q, 1K9R, 2LAW, 2LAX, 2LAY, 2LTV, 2LTW, 3KYS, 3MHR, 4RE1, 4REX
Identifiers
Aliases	YAP1, COB1, YAP, YAP2, YAP65, YKI, Yes associated protein 1, Yap
External IDs	MGI: 103262 HomoloGene: 4452 GeneCards: YAP1
Genetically Related Diseases
polycystic ovary syndrome[1]
Gene ontology Molecular function • transcription corepressor activity • transcription coactivator activity • chromatin binding • transcription factor activity, RNA polymerase II transcription factor binding • protein C-terminus binding • protein binding • transcription regulatory region DNA binding • proline-rich region binding • RNA polymerase II core promoter sequence-specific DNA binding Cellular component • cytoplasm • cytosol • membrane • transcription factor complex • nucleoplasm • nucleus Biological process • cellular response to retinoic acid • regulation of metanephric nephron tubule epithelial cell differentiation • regulation of transcription, DNA-templated • somatic stem cell population maintenance • lateral mesoderm development • bud elongation involved in lung branching • positive regulation of canonical Wnt signaling pathway • regulation of canonical Wnt signaling pathway • negative regulation of extrinsic apoptotic signaling pathway • contact inhibition • notochord development • positive regulation of organ growth • hippo signaling • transcription, DNA-templated • keratinocyte differentiation • negative regulation of stem cell differentiation • cellular response to DNA damage stimulus • vasculogenesis • regulation of cell proliferation • embryonic heart tube morphogenesis • cellular response to gamma radiation • cell morphogenesis • positive regulation of cell proliferation • lung epithelial cell differentiation • regulation of keratinocyte proliferation • transcription initiation from RNA polymerase II promoter • cell proliferation • positive regulation of stem cell population maintenance • negative regulation of epithelial cell differentiation • regulation of neurogenesis • regulation of stem cell proliferation • positive regulation of transcription from RNA polymerase II promoter • paraxial mesoderm development • negative regulation of nucleic acid-templated transcription Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10413	22601
Ensembl	ENSG00000137693	ENSMUSG00000053110
UniProt	P46937	P46938
RefSeq (mRNA)	NM_001130145 NM_001195044 NM_001195045 NM_001282097 NM_001282098 NM_001282099 NM_001282100 NM_001282101 NM_006106	NM_001171147 NM_009534
RefSeq (protein)	NP_001123617.1 NP_001181973.1 NP_001181974.1 NP_001269026.1 NP_001269027.1 NP_001269028.1 NP_001269029.1 NP_001269030.1	NP_001164618.1 NP_033560.1
Location (UCSC)	Chr 11: 102.11 – 102.23 Mb	Chr 9: 7.93 – 8 Mb
PubMed search	[2]	[3]
Wikidata

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View/Edit Mouse

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.^[4] YAP1 is a potent oncogene, which is amplified in various human cancers.^[5][6]

Structure

Modular Structure of YAP1 Isoforms

Cloning of the YAP1 gene facilitated the identification of a modular protein domain, known as the WW domain.^[7][8][9] 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.^[10][11] 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).^[12] 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).^[4][13] Following the SH3-BM is a TAD (transcription activation domain) and a PDZ domain-binding motif (PDZ-BM) (Figure 1).^[14][15]

Function

YAP1 is a transcriptional co-activator^[16] and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors,^[12] which up-regulate genes that promote cell growth and inhibit apoptosis.^[17] Several other functional partners of YAP1 were identified, including RUNX,^[16] SMADs,^[18][19] p73,^[20] ErbB4,^[21][22] TP53BP,^[23] LATS1/2,^[24] PTPN14,^[25] AMOTs,^{[26][27][28][29]} and ZO1/2.^[30] YAP1 and its close paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway.^[31] When the pathway is activated, YAP1 and TAZ are phosphorylated on a serine residue and sequestered in the cytoplasm by 14-3-3 proteins.^[31] When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate gene expression.^[31]

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.^[32]

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.^[33]

The YAP1 oncogene serves as a target for the development of new cancer drugs.^[34] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains.^[35][36] These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

References

1. "Diseases that are genetically associated with YAP1 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. Oka T, Mazack V, 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.