Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the ''MAPK15''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Evolutionarily, MAPK15 is conserved in a number of species, including ''
P. troglodytes'', ''
B. taurus'', ''
M. musculus'', ''
R. norvegicus'', ''
D. rerio'', ''
D. melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'', ''
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'' (r ...
'', and ''
X. laevis''.
Function
The protein encoded by this gene is a member of the
MAP
A map is a symbolic depiction emphasizing relationships between elements of some space, such as objects, regions, or themes.
Many maps are static, fixed to paper or some other durable medium, while others are dynamic or interactive. Although ...
(mitogen-activated protein) kinase family. MAP kinases are also known as
extracellular signal-regulated kinase
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...
s (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
carcinomas, 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 synthes ...
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 b ...
(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 DNA, wh ...
(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 living organisms acting as the most essential part for biological inheritanc ...
, and is an essential factor in protecting genome stability. MAPK15 has also been shown to regulate
ciliogenesis
Ciliogenesis is defined as the building of the cell's antenna ( primary cilia) or extracellular fluid mediation mechanism ( motile cilium). It includes the assembly and disassembly of the cilia during the cell cycle. Cilia are important organell ...
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
Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene.
Function
Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...
) 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 (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
*
*
*
*
*
*
External links
MAP Kinase Resource
{{Portal bar, Biology, border=no
EC 2.7.11