YAP1

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Modular Structure of YAP1 Isoforms

YAP1 (Yes-associated protein 1), also known as YAP or YAP65, 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, and it is one of the two main effectors of the Hippo tumor suppressor pathway.[2][3]

Modular Structure of YAP1 Protein[edit]

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]

Functional Protein Partners of YAP1[edit]

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]

YAP1 as drug target[edit]

YAP1 oncogene serves as a target for the development of new cancer drugs.[29] Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains.[30][31] These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

Mutations in YAP1 cause eye malformation[edit]

Heterozygous loss-of-function mutations 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.[32]

References[edit]

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  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. 
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  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. 
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  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. ^ a b 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. 
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  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. 
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  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. 
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  28. ^ a b c 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. ^ 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. 
  30. ^ 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. 
  31. ^ 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. 
  32. ^ 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.