YAP1



YAP1 (Yes-associated protein 1), also known as YAP or YAP65, was first identified by virtue of its ability to associate with the is_associated_with::SH3 domain of Yes and Src is_associated_with::protein-tyrosine kinases. YAP1 is a potent is_associated_with::oncogene, which is amplified in various human cancers, and it is one of the two main effectors of the Hippo is_associated_with::tumor suppressor pathway.

Modular Structure of YAP1 Protein
Cloning of the YAP1 gene facilitated the identification of a modular is_associated_with::protein domain, known as the is_associated_with::WW domain. Two splice is_associated_with::isoforms of the YAP1 gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 is_associated_with::amino acids that encoded the WW domain. Apart from the WW domain, the modular structure of YAP1 contains a is_associated_with::proline-rich region at the very is_associated_with::amino terminus, which is followed by a TID (TEAD is_associated_with::transcription factor interacting domain). 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). Following the SH3-BM is a TAD (transcription activation domain) and a is_associated_with::PDZ domain-binding motif (PDZ-BM) (Figure 1).

Functional Protein Partners of YAP1
YAP1 is a transcriptional co-activator and its proliferative and is_associated_with::oncogenic activity is driven by its association with the TEAD family of is_associated_with::transcription factors, which up-regulate genes that promote cell growth and inhibit is_associated_with::apoptosis. Several other functional partners of YAP1 were identified, including RUNX, SMADs, p73, ErbB4,  TP53BP, LATS1/2, PTPN14, AMOTs,    and ZO1/2. YAP1 and its close is_associated_with::paralog, TAZ (WWTR1), are the main effectors of the Hippo tumor suppressor pathway. When the pathway is activated, YAP1 and TAZ are is_associated_with::phosphorylated on a is_associated_with::serine residue and sequestered in the is_associated_with::cytoplasm by 14-3-3 proteins. When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate is_associated_with::gene expression.

YAP1 as drug target
YAP1 oncogene serves as a target for the development of new cancer drugs. Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains. 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
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.