YAP1

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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

File:Modular Structure of YAP1 Isoforms.jpg
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. ↑ 1.0 1.1 Sudol M (August 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): 2145–52. PMID 8035999.
  2. ↑ Huang J, Wu S, Barrera J, Matthews K, Pan D (August 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 (August 2006). "Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon". Proceedings of the National Academy of Sciences of the United States of America. 103 (33): 12405–10. Bibcode:2006PNAS..10312405O. doi:10.1073/pnas.0605579103. PMC 1533802. PMID 16894141.
  4. ↑ Bork P, Sudol M (December 1994). "The WW domain: a signalling site in dystrophin?". Trends in Biochemical Sciences. 19 (12): 531–3. doi:10.1016/0968-0004(94)90053-1. PMID 7846762.
  5. ↑ André B, Springael JY (December 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". Biochemical and Biophysical Research Communications. 205 (2): 1201–5. doi:10.1006/bbrc.1994.2793. PMID 7802651.
  6. ↑ Hofmann K, Bucher P (January 1995). "The rsp5-domain is shared by proteins of diverse functions". FEBS Letters. 358 (2): 153–7. 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 (June 1995). "Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain". The Journal of Biological Chemistry. 270 (24): 14733–41. doi:10.1074/jbc.270.24.14733. PMID 7782338.
  8. ↑ Gaffney CJ, Oka T, Mazack V, Hilman D, Gat U, Muramatsu T, Inazawa J, Golden A, Carey DJ, Farooq A, Tromp G, Sudol M (November 2012). "Identification, basic characterization and evolutionary analysis of differentially spliced mRNA isoforms of human YAP1 gene". Gene. 509 (2): 215–22. doi:10.1016/j.gene.2012.08.025. PMC 3455135. PMID 22939869.
  9. ↑ 9.0 9.1 Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML (May 2001). "TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm". Genes & Development. 15 (10): 1229–41. doi:10.1101/gad.888601. PMC 313800. PMID 11358867.
  10. ↑ Ren R, Mayer BJ, Cicchetti P, Baltimore D (February 1993). "Identification of a ten-amino acid proline-rich SH3 binding site". Science. 259 (5098): 1157–61. doi:10.1126/science.8438166. PMID 8438166.
  11. ↑ Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (May 1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Letters. 427 (1): 103–8. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608.
  12. ↑ Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Milgram SL (November 1999). "Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50". The Journal of Cell Biology. 147 (4): 879–90. doi:10.1083/jcb.147.4.879. PMC 2156157. PMID 10562288.
  13. ↑ 13.0 13.1 Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y (May 1999). "A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator". The EMBO Journal. 18 (9): 2551–62. doi:10.1093/emboj/18.9.2551. PMC 1171336. PMID 10228168.
  14. ↑ Zhao B, Kim J, Ye X, Lai ZC, Guan KL (February 2009). "Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein". Cancer Research. 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, Atfi A, Mauviel A (July 2002). "Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling". Oncogene. 21 (32): 4879–84. doi:10.1038/sj.onc.1205623. PMID 12118366.
  16. ↑ Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ (October 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, Sacchi A, Oren M, Sudol M, Cesareni G, Blandino G (May 2001). "Physical interaction with Yes-associated protein enhances p73 transcriptional activity". The Journal of Biological Chemistry. 276 (18): 15164–73. doi:10.1074/jbc.M010484200. PMID 11278685.
  18. ↑ Komuro A, Nagai M, Navin NE, Sudol M (August 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". The Journal of Biological Chemistry. 278 (35): 33334–41. doi:10.1074/jbc.M305597200. PMID 12807903.
  19. ↑ Omerovic J, Puggioni EM, Napoletano S, Visco V, Fraioli R, Frati L, Gulino A, Alimandi M (April 2004). "Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level". Experimental Cell Research. 294 (2): 469–79. doi:10.1016/j.yexcr.2003.12.002. PMID 15023535.
  20. ↑ Espanel X, Sudol M (April 2001). "Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains". The Journal of Biological Chemistry. 276 (17): 14514–23. doi:10.1074/jbc.M008568200. PMID 11278422.
  21. ↑ Oka T, Mazack V, Sudol M (October 2008). "Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP)". The Journal of Biological Chemistry. 283 (41): 27534–46. doi:10.1074/jbc.M804380200. PMID 18640976.
  22. ↑ Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, Zhang J (March 2013). "PTPN14 interacts with and negatively regulates the oncogenic function of YAP". Oncogene. 32 (10): 1266–73. doi:10.1038/onc.2012.147. PMC 4402938. PMID 22525271.
  23. ↑ Wang W, Huang J, Chen J (February 2011). "Angiomotin-like proteins associate with and negatively regulate YAP1". The Journal of Biological Chemistry. 286 (6): 4364–70. doi:10.1074/jbc.C110.205401. PMC 3039387. PMID 21187284.
  24. ↑ Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W (March 2011). "Hippo pathway-independent restriction of TAZ and YAP by angiomotin". The Journal of Biological Chemistry. 286 (9): 7018–26. 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 (January 2011). "Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein". Genes & Development. 25 (1): 51–63. doi:10.1101/gad.2000111. PMC 3012936. PMID 21205866.
  26. ↑ Oka T, Schmitt AP, Sudol M (January 2012). "Opposing roles of angiomotin-like-1 and zona occludens-2 on pro-apoptotic function of YAP". Oncogene. 31 (1): 128–34. doi:10.1038/onc.2011.216. PMID 21685940.
  27. ↑ Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M (December 2010). "Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling". The Biochemical Journal. 432 (3): 461–72. doi:10.1042/BJ20100870. PMID 20868367.
  28. ↑ 28.0 28.1 28.2 Pan D (October 2010). "The hippo signaling pathway in development and cancer". Developmental Cell. 19 (4): 491–505. doi:10.1016/j.devcel.2010.09.011. PMC 3124840. PMID 20951342.
  29. ↑ McMurray RJ, Dalby MJ, Tsimbouri PM (May 2015). "Using biomaterials to study stem cell mechanotransduction, growth and differentiation". Journal of Tissue Engineering and Regenerative Medicine. 9 (5): 528–39. doi:10.1002/term.1957. PMID 25370612.
  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, Fitzpatrick DR (February 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. PMC 3928658. PMID 24462371.
  31. ↑ Sudol M, Shields DC, Farooq A (September 2012). "Structures of YAP protein domains reveal promising targets for development of new cancer drugs". Seminars in Cell & Developmental Biology. 23 (7): 827–33. doi:10.1016/j.semcdb.2012.05.002. PMC 3427467. PMID 22609812.
  32. ↑ Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA, Liu JO, Pan D (June 2012). "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP". Genes & Development. 26 (12): 1300–5. doi:10.1101/gad.192856.112. PMC 3387657. PMID 22677547.
  33. ↑ Kang SG, Huynh T, Zhou R (2012). "Non-destructive inhibition of metallofullerenol Gd@C(82)(OH)(22) on WW domain: implication on signal transduction pathway". Scientific Reports. 2: 957. doi:10.1038/srep00957. PMC 3518810. PMID 23233876.
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