Disease relevance of YAP1

• In the present study, the expression of YAP65 in PDAC was analyzed in order to elucidate the potential role of this molecule in the pathogenesis of pancreatic cancer [1].
• Enhanced expression of YAP65 mRNA was identified by Northern blotting and quantitative RT-PCR in PDAC in comparison to the normal pancreas (2.5-fold increase) and to chronic pancreatitis (1.3-fold increase) [1].
• Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma [1].
• Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3) [2].
• We have displayed hYAP65 WW on the surface of M13 phage and randomized one-third of its three-stranded antiparallel beta-sheet [3].
• We observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers [4].
• Our findings supported that YAP1 exhibits oncogenic property in gastric cancer [5].

High impact information on YAP1

• A non-conserved isoleucine in the amino-terminal flanking region covers a hydrophobic patch and stabilizes the WW domain of human YAP65 in vitro [6].
• The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage [7].
• Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage [7].
• We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73 [7].
• Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions [7].

Biological context of YAP1

• There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1 [8].
• HSP31 is induced under conditions of oxidative stress in a YAP1-dependent manner [9].
• Co-expression of hnRNP U attenuates the ability of YAP to increase the activity of a p73-driven Bax-luciferase reporter plasmid [10].
• CONCLUSION: These data suggest that POLR2A, rRNA18S, YAP1 and ESD are the most suitable RGs for gene expression profile studies in NSCLC [11].
• Akt phosphorylation of YAP may thus suppress the induction of the proapoptotic gene expression response following cellular damage [12].

Anatomical context of YAP1

• In conclusion, YAP65 is expressed mainly in centroacinar and small ductal cells in the normal pancreas [1].
• YAP65 mRNA expression levels in human pancreatic tissue samples and cell lines were analyzed by Northern blotting and quantitative RT-PCR [1].
• In the normal pancreas, YAP65 was absent in acinar cells, large ducts and islet cells, but exhibited moderate to strong immunoreactivity in centroacinar cells and ductules [1].
• NHERF also recruits non-membrane proteins such as the c-Yes/YAP-65 complex, members of the phospholipase Cbeta family and the GRK6A protein kinase to apical surface of polarized epithelial cells where they regulate or respond to membrane signals [13].
• We propose that TAZ, as well as a highly related molecule YAP, are functionally, though not structurally, similar to beta-catenin and integrate extracellular, membrane, and cytoskeletal-derived signals to influence mesenchymal stem cell fate [14].

Associations of YAP1 with chemical compounds

• In addition, we show that the nonreceptor tyrosine kinase c-Yes is contained within EBP50 protein complexes by association with YAP65 [15].
• A constitutively active form of c-Yes was observed to decrease the binding affinity between YAP and p53BP-2 using chloramphenicol acetyltransferase/enzyme-linked immunosorbent assay, whereas the overexpression of c-Yes did not modify this interaction [16].
• One protein that associates with 14-3-3 in an Akt-dependent manner is shown here to be the Yes-associated protein (YAP), which is phosphorylated by Akt at serine 127, leading to binding to 14-3-3 [12].
• Treatment of cells with cisplatin leads to an increase in p73 accumulation and induction of apoptosis, but both were dramatically reduced in the presence of Yap1 siRNA [17].

Physical interactions of YAP1

• Here, we report that Yes-associated protein 65 (YAP65) binds with high affinity to the second EBP50 PDZ domain [15].
• Binding assays and site-specific mutagenesis have shown that the proline-rich motif binds with relatively high affinity and specificity to the WW domain of YAP, with a preliminary consensus that is different from the SH3-binding PXXP motif [18].

Regulatory relationships of YAP1

• In contrast, hnRNP U has no effect when co-expressed with a truncated YAP protein lacking the hnRNP U-binding site [10].
• In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner [19].
• The mutation is in a conserved amino acid sequence in the C terminal of the protein, a potential binding site for YAP65 one of TEAD1's cofactors that is expressed in human retina as well as TEAD1 based on RT-PCR experiments [20].

Other interactions of YAP1

• The COOH terminus of YAP65 is necessary and sufficient to mediate association with EBP50 [15].
• Furthermore, hnRNP U and YAP only interact in the nucleus, suggesting that the association between the two proteins is regulated [10].
• In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity [19].
• TGF-beta1 strongly induced Smad7 mRNA in Colo-357 and in Panc-1 cells, but only slightly induced YAP65 mRNA in Colo-357 cells [1].
• Like YAP65, TAZ interacted with all four TEF-1 family members [21].

Analytical, diagnostic and therapeutic context of YAP1

• Immunohistochemistry was carried out to localize and quantify YAP65 expression in relation to Smad7 expression and Smad4 mutations [1].
• Binding assays and site-specific mutagenesis have shown that the PY motif binds with relatively high affinity and specificity to the WW domain of YAP, with the preliminary consensus XPPXY being critical for binding [22].
• Using fluorescence in situ hybridization on human metaphase chromosomes and by analyzing rodent-human hybrids by Southern blot hybridization and polymerase chain reaction amplification, we mapped the human YAP gene to chromosome band 11q13, a region to which the multiple endocrine neoplasia type 1 gene has been mapped [23].

References