p38 mitogen-activated protein kinases are a class of
mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as
cytokines,
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
irradiation, heat shock, and
osmotic
Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of low water potential (region o ...
shock, and are involved in cell differentiation,
apoptosis and
autophagy. Persistent activation of the p38 MAPK pathway in muscle
satellite cells
Myosatellite cells, also known as satellite cells, muscle stem cells or MuSCs, are small multipotent cells with very little cytoplasm found in mature muscle. Satellite cells are precursors to skeletal muscle cells, able to give rise to satellite ...
(muscle
stem cells) due to
ageing, impairs muscle regeneration.
p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian
orthologue
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 spe ...
of the
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
Hog1p MAP kinase,
which participates in a signaling cascade controlling cellular responses to cytokines and stress.
Four p38 MAP kinases, p38-α (
MAPK14
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the ''MAPK14'' gene.
MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs ...
), -β (
MAPK11
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the ''MAPK11'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
), -γ (
MAPK12 / ERK6), and -δ (
MAPK13 / SAPK4), have been identified. Similar to the
SAPK/JNK pathway, p38 MAP kinase is activated by a variety of cellular stresses including
osmotic
Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of low water potential (region o ...
shock, inflammatory cytokines,
lipopolysaccharides
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
(LPS),
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
light, and
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
.
MKK3
Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the ''MAP2K3'' gene.
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This k ...
and
SEK activate p38 MAP kinase by
phosphorylation
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 ...
at
Thr-180 and
Tyr-182. Activated p38 MAP kinase has been shown to phosphorylate and activate
MAPKAP kinase 2 and to phosphorylate the transcription factors
ATF2
Activating transcription factor 2, also known as ATF2, is a protein that, in humans, is encoded by the ''ATF2'' gene.
Function
This gene encodes a transcription factor that is a member of the leucine zipper family of DNA-binding proteins. This ...
,
Mac,
MEF2
In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical r ...
, and
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
.
[ ] p38 also has been shown to phosphorylate post-transcriptional regulating factors like
TTP,
and in fruit flies it plays a role in regulating the circadian clock.
Clinical significance
Oxidative stress is the most powerfully specific stress activating p38 MAPK.
Abnormal activity (higher or lower than physiological) of p38 has been implicated in pathological stresses in several tissues, that include neuronal,
bone, lung, cardiac and skeletal muscle, red blood cells, and fetal tissues. The protein product of
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. RAS can increase activity of p38, and thereby cause excessively high activity of transcription factor NF-κB. This transcription factor is normally regulated from intracellular pathways that integrate signals from the surrounding tissue and the immune system. In turn these signals coordinate between cell survival and cell death. Dysregulated NF-κB activity can activate genes that cause cancer cell survival, and can also activate genes that facilitate cancer cell metastasis to other tissues.
Inhibitors
p38 inhibitors are being sought for possible therapeutic effect on autoimmune diseases and inflammatory processes,
e.g.
pamapimod.
Some have started clinical trials, e.g.
PH-797804 for
COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
. Other p38 inhibitors include BIRB 796, VX-702, SB239063, SB202190, SB203580, SCIO 469, and BMS 582949.
As of 2020,
losmapimod, a p38 inhibitor, is being investigated for the treatment of
facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, ...
(FSHD) on the basis of p38 inhibition inhibiting the effects of
DUX4
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the ''DUX4'' gene. Its misexpression is the cause of facioscapulohumeral muscular dystrophy (FSHD).
Gene
This gene is located within a D4Z4 macrosatellite repeat ...
.
References
External links
*
P38mapkPathwayp38 Signaling PathwayMAP Kinase Resource
EC 2.7.11
Protein kinases
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