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 protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular response ...

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 peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

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 ...

shock, and are involved in cell differentiation,

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

and

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

. Persistent activation of the p38 MAPK pathway in muscle satellite cells (muscle

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

s) due to

ageing Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. ...

, impairs muscle regeneration. p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue 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 constit ...

Hog1p MAP kinase, which participates in a signaling cascade controlling cellular responses to cytokines and stress. Four p38 MAP kinases, p38-α ( MAPK14), -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 Mitogen-activated protein kinase 12 (MAP kinase 12), also known as extracellular signal-regulated kinase 6 (ERK6) or stress-activated protein kinase 3 (SAPK3), is an enzyme that in humans is encoded by the ''MAPK12'' gene. Function Activation o ...

/ 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 (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 reg ...

. MKK3 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. T ...

, Mac, MEF2, and p53. 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 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 Losmapimod (GW856553X) is an investigational drug being developed by Fulcrum Therapeutics for the treatment of facioscapulohumeral muscular dystrophy (FSHD); a phase III clinical trial is pending approval. Losmapimod selectively inhibits enzy ...

, a p38 inhibitor, is being investigated for the treatment of facioscapulohumeral muscular dystrophy (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

*
P38mapkPathway

p38 Signaling Pathway

MAP Kinase Resource

EC 2.7.11 Protein kinases {{2.7-enzyme-stub