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Gene Section
Review
MAPK13 (mitogen-activated protein kinase 13)
Maria Isabel Cerezo-Guisado, Ana Cuenda
Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (MICG,
AC)
Published in Atlas Database: December 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK13ID41291ch6p21.html
DOI: 10.4267/2042/44858
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
Other names: MGC99536;
p38delta
HGNC (Hugo): MAPK13
Location: 6p21.31
Protein
PRKM13;
SAPK4;
Note
p38delta (MAPK13), also known as Stress-activated
protein kinase 4 (SAPK4) belongs to the p38 subfamily
of MAPKs.
The p38MAPK subfamily is composed by four
members encoded by different genes, which share high
sequence homologues and are designated as p38alpha
(MAPK14, or SAPK2a), p38beta (MAPK11 or
SAPK2b), p38gamma (MAPK12 or SAPK3) and
p38delta (MAPK13 or SAPK4). They are about 60%
identical in their amino acid sequence but differ in their
expression patterns, substrate specificities and
sensitivities to chemical inhibitors (Iñesta-Vaquera et
al., 2008). All p38 MAPKs are strongly activated in
vivo by environmental stresses and inflammatory
cytokines, and less by serum and growth factors.
DNA/RNA
Description
The MAPK13 entire gene spans 9.58 kb on the short
arm of chromosome 6. It contains 12 exons.
Transcription
The MAPK13 gene encodes a 365 amino-acid protein
of about 40 kDa. No splice variants have been reported.
Pseudogene
No human or mouse pseudogene known.
MAPK13 genomic context (chromosome 6, location 6p21.31).
Genomic organization of MAPK13 gene on chromosome 6p21.31. The boxes indicate coding regions (exon 1-12) of the gene.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
911
MAPK13 (mitogen-activated protein kinase 13)
Cerezo-Guisado MI, Cuenda A
Schematic representation of the p38delta (MAPK13) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif
containing the regulatory phosphorylation residues.
Description
p38delta (MAPK13) is a Serine/Threonine protein
kinase of 365 amino acids with a predicted molecular
mass of 40 kDa. It possesses the conserved amino acid
domains (I-XI) characteristic of protein kinases
(Goedert et al., 1997). The Thr180 and Tyr182 residues in
subdomain VIII are in an equivalent position to the
TXY sequence in known MAPKs. The activation of
p38delta (MAPK13) occurs via dual phosphorilation of
its TGY motif, in the activation loop, by MKK3 and
MKK6, although it is preferentially activated by MKK3
in mouse embryonic fibroblasts (Remy et al., 2009).
Expression
p38delta (MAPK13) mRNA is widely expressed with
high levels of expression in testes, pancreas, kidney and
small intestine.
Localisation
p38delta (MAPK13) localizes to the cytoplasm and
nucleus of cultured cells.
Function
p38delta (MAPK13) phosphorylates typical p38
MAPK substrates such as the transcription factors
ATF2, Elk-1 or SAP1. However, it cannot
phosphorylate MAPKAPK2 or MAPKAPK3, which
are good substrates for other p38 MAPK isoforms
(Cuenda et al., 1997; Goedert et al., 1997). p38delta
possibly plays a role in cytoskeleton regulation as it has
been reported to phosphorylate the cytoplasmic protein
stathmin, which has been linked to regulation of
microtubule dynamics (Parker et al., 1998).
Microtubule-associated protein Tau is another protein
substrate of p38delta (Goedert et al., 1997; Feijoo et al.,
2005; Yoshida and Goedert, 2006). In addition
p38delta plays a role in the regulation of protein
translation by phosphorylating and inactivating the
eukaryotic elongation factor 2 (eEF2) kinase (Knebel et
al., 2001; Knebel et al., 2002). p38delta also plays a
key role in the regulation of insulin secretion as well as
in the survival of pancreatic beta cells, since p38delta
catalyzes an inhibitory phosphorylation of the protein
kinase D1 (PDK1), which controls insuline exocytosis
in pancreatic beta cells (Sumara et al., 2009). p38delta
has been suggested to play an important role in
inducing keratinocyte differentiation by regulating the
expression of involucrin, which is a protein expressed
during keratinocyte differentiation (Eckert et al., 2003).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)
Activation of exogenously expressed p38delta by
differentiation-inducing agents such as a bioactive
green tea polyphenol (EGCG), okadaic acid (OA) or
the phorbol ester TPA, correlated with increased
involucrin promoter activity in keratinocytes via
increased activity at AP1, Sp1 and C/EBP sites
(Balasubramanian et al., 2002; Efimova et al., 2003).
The mechanisms by which p38delta may regulates
keratinocyte differentiation is still unknown, although it
has been reported that in keratinocytes expressing
exogenous p38delta this forms a complex with
ERK1/ERK2 (Efimova et al., 2003; Eckert et al.,
2004). Additional data supporting the idea that p38delta
may play a role in keratinocyte differentiation come
from a study carried out in lesional psoriasis skin
(Johansen et al., 2005). It has been shown that the
activity of p38alpha, p38beta and p38delta are
augmented in lesional psoriasis skin compared with
nonlesional psoriasis skin (Johansen et al., 2005).
Alternatively, it has been also claimed that p38delta
may have a dual role in keratinocytes contributing not
only to the differentiation process, but also to their
apoptosis in a PKCdelta dependent manner, and in
response to OA or H2O2 (Efimova et al., 2004; Kraft et
al., 2007).
Homology
p38delta (MAPK13) shows 70% identity with
p38gamma (MAPK12), 60% sequence identity with
p38alpha (MAPK14) and p38beta (MAPK11), 45%
identity with HOG1 from S. cerevisiae, 47% identity
with human SAP kinase-1 (JNK1) and 42% identity
with p42 MAPkinase (ERK2).
Implicated in
Skin cancer
Oncogenesis
It has been suggested that p38delta functions as
positive regulator of skin tumorogenesis by promoting
cell proliferation and tumor development in epidermis
(Schindler et al., 2009).
Cholangiocarcinoma
Oncogenesis
p38delta may serve as a diagnostic marker for
expression cholangiocarcinoma (CC), since its
expression is upregulated in CC relative to
912
MAPK13 (mitogen-activated protein kinase 13)
Cerezo-Guisado MI, Cuenda A
Jenkins SM, Zinnerman M, Garner C, Johnson GV. Modulation
of tau phosphorylation and intracellular localization by cellular
stress. Biochem J. 2000 Jan 15;345 Pt 2:263-70
hepatocellularcarcinoma (HCC) and to normal biliary
tract tissue (Li-Sher et al., 2009). It has been suggested
that p38delta is important for motility and invasion of
CC cells (Li-Sher et al., 2009).
Knebel A, Morrice N, Cohen P. A novel method to identify
protein kinase substrates: eEF2 kinase is phosphorylated and
inhibited by SAPK4/p38delta. EMBO J. 2001 Aug
15;20(16):4360-9
Malignant Pleural Mesothelioma
Oncogenesis
MAPK13 gene is hypermethylated in Malignant Pleural
Mesothelioma (MPM) cell lines (Goto et al., 2009).
Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H,
Shimohama S, Perry G, Smith MA. Activation of MKK6, an
upstream activator of p38, in Alzheimer's disease. J
Neurochem. 2001 Oct;79(2):311-8
Alzheimer disease
Balasubramanian S, Efimova T, Eckert RL. Green tea
polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade
to increase activator protein 1 factor-dependent involucrin gene
expression in normal human keratinocytes. J Biol Chem. 2002
Jan 18;277(3):1828-36
Note
The protein Tau is a good in vitro substrate for the p38
isoforms p38delta and p38gamma, and its
phosphorylation by these two enzymes results in a
reduction in its ability to promote microtubule
assembly (Goedert et al., 1997b; Feijoo et al., 2005).
Moreover,
overexpression
of
p38gamma
in
neuroblastoma, induces Tau phosphorylation which
correlates with a decrease on Tau associated to the
cytoskeleton and an increase of soluble Tau (Jenkins et
al., 2000). It has been reported as well that p38delta is
the major Tau kinase in neuroblastoma in response to
osmotic shock (Feijoo et al., 2005) and that the
p38MAPK activator, MKK6, has also been found to be
active in neurodegenerative diseases (Zhu et al., 2001).
Moreover, oxidant agents implicated in Alzheimer's
disease can cause hyperphosphorylation in rat brain and
also induce the activation of p38delta, indicating that
this kinase may be involved in Tau phosphorylation
(Yin et al., 2006). On the other hand, it has been shown
using phosphospecific antibodies that p38MAPKs
phosphorylate Tau on residues phosphorylated in a Tau
obtained from patients suffering Alzheimer's disease
(Goedert et al., 1997b; Feijoo et al., 2005).
Knebel A, Haydon CE, Morrice N, Cohen P. Stress-induced
regulation of eukaryotic elongation factor 2 kinase by SB
203580-sensitive and -insensitive pathways. Biochem J. 2002
Oct 15;367(Pt 2):525-32
Eckert RL, Efimova T, Balasubramanian S, Crish JF, Bone F,
Dashti S. p38 Mitogen-activated protein kinases on the body
surface--a function for p38 delta. J Invest Dermatol. 2003
May;120(5):823-8
Efimova T, Broome AM, Eckert RL. A regulatory role for p38
delta MAPK in keratinocyte differentiation. Evidence for p38
delta-ERK1/2 complex formation. J Biol Chem. 2003 Sep
5;278(36):34277-85
Eckert RL, Crish JF, Efimova T, Balasubramanian S.
Antioxidants
regulate
normal
human
keratinocyte
differentiation. Biochem Pharmacol. 2004 Sep 15;68(6):112531
Efimova T, Broome AM, Eckert RL. Protein kinase Cdelta
regulates keratinocyte death and survival by regulating activity
and subcellular localization of a p38delta-extracellular signalregulated kinase 1/2 complex. Mol Cell Biol. 2004
Sep;24(18):8167-83
Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A.
Evidence that phosphorylation of the microtubule-associated
protein Tau by SAPK4/p38delta at Thr50 promotes microtubule
assembly. J Cell Sci. 2005 Jan 15;118(Pt 2):397-408
Diabetes type 2 (diabetes mellitus)
Note
p38delta plays a key role in the regulation of insulin
secretion as well as in the survival of pancreatic beta
cells (Sumara et al., 2009).
Johansen C, Kragballe K, Westergaard M, Henningsen J,
Kristiansen K, Iversen L. The mitogen-activated protein
kinases p38 and ERK1/2 are increased in lesional psoriatic
skin. Br J Dermatol. 2005 Jan;152(1):37-42
References
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Melatonin
arrests
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MAPK13 (mitogen-activated protein kinase 13)
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This article should be referenced as such:
Cerezo-Guisado MI, Cuenda A. MAPK13 (mitogen-activated
protein kinase 13). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(10):911-914.
914