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.
The Hippo/YAP signaling pathway may exert neuroprotective effects through mitigating blood-brain barrier disruption after cerebral ischemia/reperfusion injury.[34]
References
↑ 1.01.1Sudol 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. PMID8035999.
↑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. PMID16096061.
↑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. PMID7846762.
↑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. PMID7802651.
↑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. PMID7828727.
↑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. PMID7782338.
↑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. PMID19141641.
↑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. PMID11278685.
↑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. PMID12807903.
↑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. PMID15023535.
↑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. PMID11278422.
↑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. PMID18640976.
↑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. PMID21685940.
