Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''MAPK15''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Evolutionarily, MAPK15 is conserved in a number of species, including ''
P. troglodytes'', ''
B. taurus'', ''
M. musculus'', ''
R. norvegicus'', ''
D. rerio'', ''
D. melanogaster'', ''
C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'', and ''
X. laevis''.
Function
The protein encoded by this gene is a member of the
MAP
A map is a symbolic depiction of interrelationships, commonly spatial, between things within a space. A map may be annotated with text and graphics. Like any graphic, a map may be fixed to paper or other durable media, or may be displayed on ...
(mitogen-activated protein) kinase family. MAP kinases are also known as
extracellular signal-regulated kinases (ERKs), and are involved in signaling cascades that regulate a number of cellular processes, including proliferation, differentiation, and transcriptional regulation. MAPK15 is often referred to as ERK7 or ERK8, and the latter two share 69% amino acid sequence similarity; at least one study has suggested that the two are, in fact, distinct proteins.
In vertebrate models, ERK8 is not constitutively active, and exhibits relatively low basal kinase activity.
It contains two SH3 (
SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway.
SRC is a non-receptor tyrosine kinase (and
proto-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. ) that has been implicated in cancer growth and progression in humans when it is overexpressed. The exact function of MAPK15 is unknown, though a number of studies have implicated the enzyme in various cellular pathways.
Specifically, MAPK15 expression is significantly reduced in human lung and breast
carcinoma
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoder ...
s, and MAPK15 down-regulation is correlated with increased cell motility.
MAPK15 has also been found to negatively regulate protein
O-glycosylation
''O''-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. ''O''-glycosylation is a post-translational modification that occurs after the protein has been synthesis ...
with acetyl galactosamine (GalNAc), a process in which a sugar molecule is covalently attached to an oxygen atom on an amino acid residue.
Mammalian MAPK15 is a putative regulator of the cellular localization and transcriptional activity of
estrogen-related receptor alpha
Estrogen-related receptor alpha (ERRα), also known as NR3B1 (nuclear receptor subfamily 3, group B, member 1), is a nuclear receptor that in humans is encoded by the ''ESRRA'' (Estrogen Related Receptor Alpha) gene. ERRα was originally cloned ...
(ERRa), as well as an inhibitor of
proliferating cell nuclear antigen
Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the D ...
(PCNA) degradation. PCNA is critical for
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
, and is an essential factor in protecting genome stability. MAPK15 has also been shown to regulate
ciliogenesis in ''
X. laevis'' (African clawed frog) embryos by phosphorylating an actin regulator called CapZIP.
Interactions
MAPK15 has been demonstrated to interact with gamma-aminobutyric acid receptor-associated protein (
GABARAP) and microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A, or LC3) in a process that stimulates autophagy. A number of additional proteins also interact with MAPK15, including
cyclin-dependent kinase 2
Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
(CDK2), mitogen-activated protein kinase 12 (MAPK12), and lactotransferrin (LTF), among many others.
Clinical significance
Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics.
Additionally, given the putative role that MAPK15 plays in the regulation of ciliogenesis, it may be an ideal target for diseases related to human ciliary defects (often called
ciliopathies).
References
Further reading
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External links
MAP Kinase Resource
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EC 2.7.11