YAP1 (Yes-associated protein 1, 65kDa)

2010-01-01   Silvia Di Agostino , Sabrina Strano , Giovanni Blandino 

Molecular Medicine Department, Regina Elena Cancer Institute, Rome 00144, Italy

Identity

HGNC
LOCATION
11q22.1
LOCUSID
ALIAS
COB1,YAP,YAP2,YAP65,YKI
FUSION GENES

DNA/RNA

Atlas Image
YAP1 mRNA spans approximately 5218 bases and has 7 exons.

Description

The genomic size is 122863 bases and the gene is located on plus strand. YAP1 gene is composed of 7 exons. The open reading frame of the coding region is 1364 bp. No polymorphisms of YAP1 is known.
SNP: 1590 single nucleotide polymorphisms are present in the human gene according to NCBI database.

Transcription

The human YAP1 coding sequence consists of 1364 bp from the start codon to the stop codon. A differentially spliced isoform of YAP1 (9 exons), with two WW domains known as YAP2 also exists (Sudol et al., 1995).

Pseudogene

No pseudogene of YAP1 is known.

Proteins

Note

The Yes-associated protein (YAP), a critical mediator of p73 function, binds p73 to regulate its transcriptional activity (Strano et al., 2001) and subsequent cell-death induction (Basu et al., 2003). This binding is negatively regulated by AKT-mediated YAP phosphorylation (Basu et al., 2003) and enhanced by DNA damage (Strano et al., 2005). In addition to increase p73 transcriptional activity via the p300 acetyltansferase (Strano et al., 2005), YAP can stabilize p73 protein in a posttranslational manner by competing with the ITCH E3-ligase for binding to p73 (Levy et al., 2007).
Atlas Image
Structure of human YAP isoforms. The protein domains and their length (indicated by number of limiting residues) are reported. YAP1 contains a proline-rich domain, a WW domain, a glutamine rich domain and portion of protein that regulates the transcription activation.

Description

Structure: YAP protein consists of 454 amino acids, with a molecular weight of 65 kDa. It was identified as a protein that interacted with the non receptor tyrosine kinase c-Yes, which is a member of the Src family (Sudol, 1994). In fact, Yap is able to interact with the SH3 domain of c-Yes (and also c-Src), through a stretch of proline residues; this proline-rich region is able to interact with SH3 domains of many other proteins. In addition Yap contains another binding domain of a different nature. Due to the presence of two tryptophan residues, which appear to be conserved along evolution and that play an important role in the domain structure and function, it was named WW domain (Sudol et al., 1995; Sudol and Hunter, 2000).
The WW domain binds to short stretches of prolines (PY motif), and therefore mediating the interaction between proteins. The WW domain of Yap belongs to the first of four different classes that differ in terms of the sequence of the interacting motif, a PPxY in the case of WW type I. Yap has been found to interact with many proteins, whose function often is quite substantially different, and the majority of these interactions are mostly mediated by the WW domain (Bertini et al., 2009).
The interaction with PEBP2 (a RunX transcription factor) was the first example of Yap1 as a co-activator of transcription. The WW domain of Yap1 interacts with the PY motif present in the transcription activation domain of PEBP2 and in this occasion Yap1 was reported for the first time to have a strong intrinsic transactivation activity (Yagi et al., 1999). The transcriptional coactivator Yes-associated protein (YAP) was shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage (Strano et al., 2001; Strano et al., 2005).
Interactors of YAPReference
YES Sudol et al., 1995
WBP1 and WBP2Chen and Sudol, 1995
NFE2Gavva et al., 1997
RUNX1 and RUNX2Yagi et al., 1999
EBP50Mohler et al., 1999
TP53BP2Espanel and Sudol, 2001
TP73 Strano et al., 2001
TEAD1, 2, 3, 4 Vassilev et al., 2001
SMAD7Ferrigno et al., 2002
AKTBasu et al., 2003
ERBB4Komuro et al., 2003
HNRNPUHowell et al., 2004
LATS1Hao et al., 2008
ABL1Levy et al., 2008
PMLLapi et al., 2008
EGR1Zagurovskaya et al., 2009
Table 1: Modified by Bertini et al., 2009.

Expression

By Northern blot analysis YAP1 expression shows a major transcript of approximately 5 kb in several human tissues. High expression was found in placenta, prostate, testis, ovary, and small intestine, and lower expression was found in brain, liver, and spleen. No expression was found in peripheral blood leukocytes (Sudol et al., 1995).
YAP1 is the predominant isoform and is ubiquitously expressed in the major part of tissues for twelve normal human tissues (out of 28 tissues shown) hybridized against Affymetrix GeneChips HG-U95A-E (GeneNote data) and for 22 normal human tissues hybridized against HG-U133A (GNF Symatlas data) (Su et al., 2004).

Localisation

Posttranslational modification of YAP determines its binding and localisation. Lapi et al. (2008) have shown Akt-mediated phosphorylation promotes YAP cytoplasmic retention, demonstrating that active Akt counters cisplatin-induced increases in PML transcription via the YAP-p73 complex. Recently, Levy et al. (2008) have also shown that cisplatin induces ABL1-mediated YAP phosphorylation, resulting in YAP nuclear localization and increased p73 binding and activation of pro-apoptotic genes.
YAP binding of p73 and its coordination of other binding proteins probably depend on an integration of phosphorylation by AKT, ABL1, and other kinases. However, the shuttling of Yap between nucleus and cytoplasm has emerged as an important means for regulating the activity of this protein.

Function

Yap is a small protein that binds to many transcription factors and modulates their activity. Yap increases the ability of p73 to induce apoptosis as a consequence of damage to the DNA, and therefore its activity was thought to favor tumor suppression. However, other studies have recently shown a role for Yap in cell differentiation, cell transformation and in the regulation of organ size. It has been demonstrated that the Drosophila Hippo pathway has a mammalian equivalent, and that Yap is part of this pathway, where it could stimulate proliferation (Pan, 2007; Harvey et al., 2007).
Apoptosis: The transcriptional coactivator Yes-associated protein (YAP) has demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage (Strano et al., 2001; Strano et al., 2005). It has been reported that YAP is phosphorylated by AKT, and such modification impairs YAP-nuclear translocation and attenuates p73-mediated apoptosis (Basu et al., 2003). Recently, it was demonstrated that p73 is required for the nuclear translocation of endogenous YAP in cells exposed to cisplatin and that YAP is recruited by PML into nuclear bodies to promote p73 transcriptional activity (Strano et al., 2005). It was found that YAP contributes to p73 stabilization in response to DNA damage and promotes p73-dependent apoptosis through the specific and selective coactivation of apoptotic p73 target genes and potentiation of p300-mediated acetylation of p73 (Strano et al., 2005). Then, it was described the existence of a proapoptotic autoregulatory feedback loop between p73, YAP, and the promyelocytic leukemia (PML) tumor suppressor gene (Lapi et al., 2008). PML is a direct transcriptional target of p73/YAP. PML contributes to the p73-dependent apoptotic response by regulating YAP stability. Importantly, PML and YAP physically interact through their PVPVY and WW domains, respectively, causing YAP stabilization upon cisplatin treatment, which occurs through PML mediated sumoylation (Lapi et al., 2008).
Together with this proapoptotic role, YAP recently was identified as a tumor suppressor in breast cancer (Yuan et al., 2008). The findings that YAP plays opposing roles in tissue growth/development and DNA damage/apoptosis appear at first contradictory, but this can be explained if YAP binds and activates or inactivates different transcription factors to differentially regulate either pro-growth or pro-apoptotic genes.
Organ size and cell differentiation: Yap plays an important role in controlling organ growth. The works done on Drosophila show how a disrupted Hippo signalling pathway has a negative impact on the growth of imaginal discs (Pan et al., 2007) and how the presence of mutated forms of Yap in particular has an effect on size and shape of fly wings (Zhao et al., 2007).
In addition Dong et al. (2007) reported that overexpression of Yap in mice increases liver size, and in the long term it induces nodules which present characteristics of HCC (Dong et al., 2007). This is in accordance with another important study where increased levels of Yap are shown to enlarge liver size in a reversible manner (Camargo et al., 2007).
However, many questions are unsolved. For instance, it would be interesting to check whether the Hippo pathway plays a role in choices taken by Yap during cell differentiation; to verify whether activity of Yap could be extended to a cellular context beside intestine epithelium; to find the molecular mechanism used by Yap to control transcription of those genes that are in charge of cell differentiation; and obviously, a screen for these genes.

Homology

Orthologs: YAP1 is evolutionarily principally conserved in 8 eukaryotes: Canis familiaris, Pan troglodytes, Bos taurus, Mus musculus, Galus gallus, Danio rerio, Xenopus laevis, Silurana tropicalis. Orthologies between human and Drosophyla melanogaster, Caenorabditis elegans and Saccaromyces cerevisiae are quite low. For details see: HomoloGene.

Mutations

Note

No mutations of YAP1 are known.

Implicated in

Entity name
Various cancers
Note
Overholtzer and collaborators identified a mouse mammary tumor with a small amplicon involving the Yap1 gene. They noted that amplification of the syntenic locus on human chromosome 11q22 is present in different cancers (breast, colon, prostate). Overexpression of human YAP1 in nontransformed mammary epithelial cells induced epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar (Overholtzer et al., 2006). They concluded that YAP1 contributes to malignant transformation in cancers harboring the 11q22 amplicon.
Entity name
Tumor suppression
Note
As previously described, the regulation of p73 activity by YAP has been investigated in the context of DNA-damage signaling. As an activating cofactor for a proapoptotic transcription factor, it was assumed that YAP plays a tumor suppressor role in cancer. YAP has also been identified as an oncogenic progrowth, cell size regulator in both Drosophila melanogaster and mammalian cells (Dong et al., 2007; Zhao et al., 2007). The mechanism for the growth control role of YAP or its fly homolog, Yki, is the result of its inactivation by the MST2 (HIPPO in fly) pathway, where the tumor suppressor LATS1 kinase (WTS in fly) directly phosphorylates YAP (Yki), inhibiting its coactivation of the TEAD (Scalloped in fly) transcription factor to upregulate pro-growth genes (Zhao et al., 2008).
The MST2/LATS1 pathway can also enhance YAP-p73 binding and activation of proapoptotic genes downstream of Fas signaling in breast cancer cells (Matallanas et al., 2007).

Bibliography

Pubmed IDLast YearTitleAuthors
125355172003Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis.Basu S et al
191066012009YAP: at the crossroad between transformation and tumor suppression.Bertini E et al
179805932007YAP1 increases organ size and expands undifferentiated progenitor cells.Camargo FD et al
76444981995The WW domain of Yes-associated protein binds a proline-rich ligand that differs from the consensus established for Src homology 3-binding modules.Chen HI et al
178896542007Elucidation of a universal size-control mechanism in Drosophila and mammals.Dong J et al
103580881999A single point mutation in a group I WW domain shifts its specificity to that of group II WW domains.Espanel X et al
121183662002Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling.Ferrigno O et al
93058521997Interaction of WW domains with hematopoietic transcription factor p45/NF-E2 and RNA polymerase II.Gavva NR et al
181582882008Tumor suppressor LATS1 is a negative regulator of oncogene YAP.Hao Y et al
173182112007The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.Harvey K et al
150965132004Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription.Howell M et al
128079032003WW 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.Komuro A et al
191116602008PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop.Lapi E et al
182802402008Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage.Levy D et al
178896692007RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein.Matallanas D et al
105622881999Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50.Mohler PJ et al
168941412006Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.Overholtzer M et al
174379952007Hippo signaling in organ size control.Pan D et al
158937282005The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage.Strano S et al
112786852001Physical interaction with Yes-associated protein enhances p73 transcriptional activity.Strano S et al
150753902004A gene atlas of the mouse and human protein-encoding transcriptomes.Su AI et al
77823381995Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain.Sudol M et al
111631762000NeW wrinkles for an old domain.Sudol M et al
80359991994Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product.Sudol M et al
113588672001TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm.Vassilev A et al
102281681999A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator.Yagi R et al
186178952008Yes-associated protein (YAP) functions as a tumor suppressor in breast.Yuan M et al
191370132009EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells.Zagurovskaya M et al
179749162007Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.Zhao B et al
185797502008TEAD mediates YAP-dependent gene induction and growth control.Zhao B et al

Other Information

Locus ID:

NCBI: 10413
MIM: 606608
HGNC: 16262
Ensembl: ENSG00000137693

Variants:

dbSNP: 10413
ClinVar: 10413
TCGA: ENSG00000137693
COSMIC: YAP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000137693ENST00000282441P46937
ENSG00000137693ENST00000345877P46937
ENSG00000137693ENST00000524575P46937
ENSG00000137693ENST00000526343P46937
ENSG00000137693ENST00000529029H0YCI3
ENSG00000137693ENST00000531439P46937
ENSG00000137693ENST00000537274P46937
ENSG00000137693ENST00000615667P46937
ENSG00000137693ENST00000629586P46937
ENSG00000137693ENST00000629586A0A024R3E4

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Hippo signalingKEGGhsa_M00683
Hippo signalingKEGGM00683
Signal TransductionREACTOMER-HSA-162582
Signaling by ERBB4REACTOMER-HSA-1236394
Nuclear signaling by ERBB4REACTOMER-HSA-1251985
Signaling by HippoREACTOMER-HSA-2028269
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
YAP1- and WWTR1 (TAZ)-stimulated gene expressionREACTOMER-HSA-2032785
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
216547992011Role of YAP/TAZ in mechanotransduction.1302
178896542007Elucidation of a universal size-control mechanism in Drosophila and mammals.861
179805932007YAP1 increases organ size and expands undifferentiated progenitor cells.486
200480012010A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).443
239544132013A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.411
168941412006Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.380
255926482015The emerging roles of YAP and TAZ in cancer.345
181582882008Tumor suppressor LATS1 is a negative regulator of oncogene YAP.339
273004342016YAP/TAZ at the Roots of Cancer.332
228954352012Transduction of mechanical and cytoskeletal cues by YAP and TAZ.268

Citation

Silvia Di Agostino ; Sabrina Strano ; Giovanni Blandino

YAP1 (Yes-associated protein 1, 65kDa)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/42855/yap1