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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]


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  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.