p38 mitogen-activated protein kinases are a class of

mitogen-activated protein kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamma ...

s (MAPKs) that are responsive to stress stimuli, such as

cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

ultraviolet Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...

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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

and

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

. 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 satellit ...

(muscle

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

s) due to

ageing Ageing (or aging in American English) is the process of becoming older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentially biol ...

, 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 speci ...

of the

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

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 MAP ...

), -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

shock, inflammatory cytokines,

lipopolysaccharides Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

(LPS),

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 regu ...

. MKK3 and SEK activate p38 MAP kinase by

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

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 Mac or MAC may refer to: Common meanings * Mac (computer), a line of personal computers made by Apple Inc. * Mackintosh, a raincoat made of rubberized cloth * Mac, a prefix to surnames derived from Gaelic languages * McIntosh (apple), a Canadi ...

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 rol ...

, and

p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

. 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. P38 was also shown to correlate with outcome of

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...

- higher pathway activity is associated with low survival.

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 chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...

. 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 fac ...

(FSHD) on the basis of p38 inhibition inhibiting the effects of DUX4.

References

External links

*
P38mapkPathway

p38 Signaling Pathway

MAP Kinase Resource

{{Portal bar, Biology, border=no EC 2.7.11 Protein kinases