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Gene Section
Review
YAP1 (Yes-associated protein 1, 65kDa)
Silvia Di Agostino, Sabrina Strano, Giovanni Blandino
Molecular Medicine Department, Regina Elena Cancer Institute, Rome 00144, Italy (SD, SS, GB)
Published in Atlas Database: January 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/YAP1ID42855ch11q22.html
DOI: 10.4267/2042/44893
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
- MMP20, matrix metalloproteinase 20, 11q22.2
Note: YAP interacts with the SH3 domain of c-Yes
(and also c-Src), through a stretch of proline residues.
YAP protein contains a WW domain that is found in
various structural, regulatory and signaling molecules
in yeast, nematode, and mammals, and it is involved in
protein-protein interaction.
Other names: YAP; YAP2; YAP65; YKI
HGNC (Hugo): YAP1
Location: 11q22.1
Local order: Genes flanking YAP1 on 11q22.1 are:
- CNTN5, contactin-5, 11q22.1
- FLJ42335, Hypothetical protein LOC100128386,
11q22.1
- FLJ32810, Rho-type GTPase-activating protein
FLJ32810, 11q22.1
- TMEM133, transmembrane protein 133, 11q22.1
- PGR, progesterone receptor, 11q22-q23
- TRPC6, transient receptor potential cation channel,
subfamily C, member 6, 11q22.1
- ANGPTL5, angiopoietin-like 5, 11q22.1
- YAP1, Yes-associated protein 1, 11q22.1
- RPS6P17, ribosomal protein S6 pseudogene 17,
11q22.2
- BIRC3, baculoviral IAP repeat-containing protein 3,
11q22.2
- BIRC2, baculoviral IAP repeat-containing protein 2,
11q22.2
DNA/RNA
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 polymorphism 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.
YAP1 mRNA spans approximately 5218 bases and has 7 exons.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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YAP1 (Yes-associated protein 1, 65kDa)
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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.
Protein
Interactors of YAP
Reference
YES
Sudol et al., 1995
WBP1 and WBP2
Chen and Sudol, 1995
NFE2
Gavva et al., 1997
RUNX1 and RUNX2
Yagi et al., 1999
EBP50
Mohler et al., 1999
TP53BP2
Espanel and Sudol, 2001
TP73
Strano et al., 2001
TEAD1, 2, 3, 4
Vassilev et al., 2001
SMAD7
Ferrigno et al., 2002
Description
AKT
Basu et al., 2003
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 p73dependent apoptosis in response to DNA damage
(Strano et al., 2001; Strano et al., 2005).
ERBB4
Komuro et al., 2003
HNRNPU
Howell et al., 2004
LATS1
Hao et al., 2008
ABL1
Levy et al., 2008
PML
Lapi et al., 2008
EGR1
Zagurovskaya et al., 2009
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 Genet Cytogenet Oncol Haematol. 2010; 14(11)
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
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YAP1 (Yes-associated protein 1, 65kDa)
Di Agostino S, et al.
differentially regulate either pro-growth or proapoptotic 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.
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 Yesassociated 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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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
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-tomesenchymal 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.
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YAP1 (Yes-associated protein 1, 65kDa)
Di Agostino S, et al.
Tumor suppression
cytoplasm. Genes Dev. 2001 May 15;15(10):1229-41
Note
As previously described, the regulation of p73 activity
by YAP has been investigated in the context of DNAdamage 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).
Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J,
Atfi A, Mauviel A. Yes-associated protein (YAP65) interacts
with Smad7 and potentiates its inhibitory activity against TGFbeta/Smad signaling. Oncogene. 2002 Jul 25;21(32):4879-84
Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt
phosphorylates the Yes-associated protein, YAP, to induce
interaction with 14-3-3 and attenuation of p73-mediated
apoptosis. Mol Cell. 2003 Jan;11(1):11-23
Komuro A, Nagai M, Navin NE, Sudol M. WW domaincontaining 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. J Biol Chem. 2003
Aug 29;278(35):33334-41
Howell M, Borchers C, Milgram SL. Heterogeneous nuclear
ribonuclear protein U associates with YAP and regulates its coactivation of Bax transcription. J Biol Chem. 2004 Jun
18;279(25):26300-6
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D,
Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP,
Walker JR, Hogenesch JB. A gene atlas of the mouse and
human protein-encoding transcriptomes. Proc Natl Acad Sci U
S A. 2004 Apr 20;101(16):6062-7
Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G,
Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, Del Sal G,
Levrero M, Blandino G. The transcriptional coactivator Yesassociated protein drives p73 gene-target specificity in
response to DNA Damage. Mol Cell. 2005 May 13;18(4):44759
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Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC,
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This article should be referenced as such:
Di Agostino S, Strano S, Blandino G. YAP1 (Yes-associated
protein 1, 65kDa). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(11):1054-1058.
Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY,
Chinnaiyan AM, Lai ZC, Guan KL. TEAD mediates YAP-
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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