YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a
transcription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription ar ...
that promotes transcription of genes involved in
cellular proliferation and suppressing
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
genes. YAP1 is a component in the
hippo signaling pathway
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its k ...
which regulates organ size, regeneration, and tumorigenesis. YAP1 was first identified by virtue of its ability to associate with the
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...
of
Yes and
Src protein
tyrosine kinases
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
.
''YAP1'' is a potent
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , which is amplified in various human cancers.
Structure
![Modular Structure of YAP1 Isoforms](https://upload.wikimedia.org/wikipedia/commons/7/7c/Modular_Structure_of_YAP1_Isoforms.jpg)
Cloning of the YAP1 gene facilitated the identification of a modular
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
, known as the
WW domain
The WW domain, (also known as the rsp5-domain or WWP repeating motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be ...
.
Two splice
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
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
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
that encoded the WW domain.
Apart from the WW domain, the modular structure of YAP1 contains a
proline-rich region at the very
amino terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
, which is followed by a TID (TEAD
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
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 (
transactivation domain
The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation ...
) and a
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to ...
-binding motif (PDZ-BM) (Figure 1).
Function
YAP1 is a transcriptional co-activator
and its proliferative and
oncogenic
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
activity is driven by its association with the TEAD family of
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
,
which up-regulate genes that promote cell growth and inhibit
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Several other functional partners of YAP1 were identified, including RUNX,
SMADs,
p73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized ...
,
ErbB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ''ERBB4'' gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characteriz ...
,
TP53BP2
Apoptosis-stimulating of p53 protein 2 (ASPP2) also known as Bcl2-binding protein (Bbp) and tumor suppressor p53-binding protein 2 (p53BP2) is a protein that in humans is encoded by the ''TP53BP2'' gene. Multiple transcript variants encoding differ ...
,
LATS1
Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the ''LATS1'' gene.
It has been associated with the Hippo signaling pathway, where it phosphorylates YAP and TAZ to inactivate their function.
The protein encoded ...
/
2,
PTPN14
Tyrosine-protein phosphatase non-receptor type 14 is an enzyme that in humans is encoded by the ''PTPN14'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase, PTP family anPTPN14subfamily of tyrosin ...
,
AMOT
Angiomotin (AMOT) is a protein that in humans is encoded by the ''AMOT'' gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 ( AMOTL1) and angiomotin-like 2 ( AMOTL2) characterized by ...
s,
and
ZO1/
2.
YAP1 and its close
paralog
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
, TAZ (
WWTR1
WW domain-containing transcription regulator protein 1 (WWTR1), also known as Transcriptional coactivator with PDZ-binding motif (TAZ), is a protein that in humans is encoded by the ''WWTR1'' gene. WWTR1 acts as a transcriptional coregulator a ...
), are the main effectors of the Hippo tumor suppressor pathway.
When the pathway is activated, YAP1 and TAZ are
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
on a
serine residue and sequestered in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
by
14-3-3 proteins.
When the Hippo pathway is not activated, YAP1/TAZ enter the nucleus and regulate
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
.
It is reported that several genes are regulated by YAP1, including
Birc2
Baculoviral IAP repeat-containing protein 2 (also known as cIAP1) is a protein that in humans is encoded by the ''BIRC2'' gene.
Function
cIAP1 is a member of the Inhibitor of Apoptosis family that inhibit apoptosis by interfering with the acti ...
,
Birc5
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the ''BIRC5'' gene.
Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions ...
, connective tissue growth factor (
CTGF
CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). CTGF has important roles in many ...
),
amphiregulin (AREG),
Cyr61
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the ''CYR61'' gene.
CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...
,
Hoxa1 and
Hoxc13.
YAP/TAZ have also been shown to act as stiffness sensors, regulating mechanotransduction independently of the Hippo signalling cascade.
As YAP and TAZ are transcriptional co-activators, they do not have DNA-binding domains. Instead, when inside the nucleus, they regulate gene expression through TEAD1-4 which are sequence-specific transcription factors that mediate the main transcriptional output of the Hippo pathway. The YAP/TAZ and TEAD interaction competitively inhibits and actively dissociates the TEAD/
VGLL4
Vestigial like family member 4 is a protein that in humans is encoded by the VGLL4 gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' ...
interaction which functions as a transcriptional repressor. Mouse models with YAP over-expression have been shown to exhibit up-regulation of the TEAD target gene expression which results in increased expansion of progenitor cells and tissue overgrowth.
Regulation
Biochemical
![YAP and TAZ - Biochemical Regulation Diagram](https://upload.wikimedia.org/wikipedia/commons/d/dc/YAP_and_TAZ_-_Biochemical_Regulation_Diagram.png)
At the biochemical level, YAP is part of and regulated by the Hippo signaling pathway where a kinase cascade results in its “inactivation”, along with that of TAZ. In this signaling cascade, TAO kinases phosphorylate Ste20-like kinases,
MST1
Macrophage-stimulating protein (MSP), also known as hepatocyte growth factor-like protein (HLP, HGFL, or HGFLP), is a protein that in humans is encoded by the ''MST1'' (''macrophage-stimulating 1'') gene
In biology, the word gene (from , ...
/
2, at their activation loops (Thr183 for MST1 and Thr180 for MST2). Active MST1/2 then phosphorylate
SAV1
Protein salvador homolog 1 is a protein that in humans is encoded by the ''SAV1'' gene.
WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protei ...
and
MOB1A
MOB kinase activator 1A is an enzyme that in humans is encoded by the ''MOB1A'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ' ...
/
B which are scaffold proteins that assist in the recruitment and phosphorylation of LATS1/2. LATS1/2 can also be phosphorylated by two groups of
MAP4K Mitogen-activated protein kinase kinase kinase kinase (MAP4K) is a family of proteins involved in cellular signal transduction.
* MAP4K1 (aka HPK1)
* MAP4K2 (aka GCK)
* MAP4K3 (aka GLK)
* MAP4K4 (aka HGK)
* MAP4K5 (aka KHS)
* MAP4K6 (aka MINK ...
s. LATS1/2 then phosphorylate YAP and TAZ which causes them to bind with 14-3-3, resulting in cytoplasmic sequestration of YAP and TAZ. The result of the activation of this pathway is the restriction of YAP/TAZ from entering the cell nucleus.
Mechanotransductive
Additionally, YAP is regulated by mechanical cues such as extracellular matrix (ECM) rigidity, strain, shear stress, or adhesive area, processes that are reliant on cytoskeletal integrity.
These mechanically induced localization phenomena are thought to be the result of nuclear flattening induced pore size change, mechanosensitive nuclear membrane ion channels, mechanical protein stability, or a variety of other factors.
These mechanical factors have also been linked to certain cancer cells via nuclear softening and higher ECM stiffnesses.
Under this framework, the nuclear softening phenotype of cancer cells would promote nuclear flattening in response to a force, causing YAP localization, which could explain its over-expression and promoted proliferation in oncogenic cells.
Additionally, the higher ECM stiffness phenotype commonly seen in tumors due to enhanced integrin signaling
could flatten the cell and nucleus, once again causing higher YAP nuclear localization. Likewise, the opposite effect of nuclear stiffening as a result of a variety of stimuli such as an over-expression of
lamin A
Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins.
Function
In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...
, has been shown to decrease nuclear YAP localization.
Clinical significance
Cancer
Dysregulation of YAP/TAZ-mediated transcriptional activity is implicated in the development of abnormal cell growth and hyperactivation of YAP and TAZ has been observed amongst many cancers.
Hence YAP1 represents a potential target for the treatment of cancer.
While YAP has been identified as a proto-oncogene, it can also act as a tumor suppressor depending on cellular context.
As a drug target
The 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.
Neuroprotection
The Hippo/YAP signaling pathway may exert
neuroprotective
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
effects through mitigating
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
disruption after cerebral ischemia/reperfusion injury.
Mutations
Heterozygous loss-of-function mutations in the ''YAP1'' gene 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.
External links
*
*
References
{{Hippo signaling pathway
Genes on human chromosome 11
Transcription factors