P38 mitogen-activated protein kinases


Main article: Mitogen-activated protein kinase
mitogen-activated protein kinase 11
Identifiers
Symbol MAPK11
Alt. symbols PRKM11
NCBI gene 5600
HGNC 6873
OMIM 602898
RefSeq NM_002751
UniProt Q15759
Other data
EC number 2.7.11.24
Locus Chr. 22 q13.33
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Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 12
Identifiers
Symbol MAPK12
Alt. symbols SAPK3
NCBI gene 6300
HGNC 6874
OMIM 602399
RefSeq NM_002969
UniProt P53778
Other data
EC number 2.7.11.24
Locus Chr. 22 q13.3
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Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 13
Identifiers
Symbol MAPK13
Alt. symbols PRKM13
NCBI gene 5603
HGNC 6875
OMIM 602899
RefSeq NM_002754
UniProt O15264
Other data
EC number 2.7.11.24
Locus Chr. 6 p21
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Structures Swiss-model
Domains InterPro
mitogen-activated protein kinase 14
Identifiers
Symbol MAPK14
Alt. symbols CSPB1, CSBP1, CSBP2
NCBI gene 1432
HGNC 6876
OMIM 600289
RefSeq NM_001315
UniProt Q16539
Other data
EC number 2.7.11.24
Locus Chr. 6 p21.3-21.2
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Structures Swiss-model
Domains InterPro

p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Persistent activation of the p38 MAPK pathway in muscle satellite cells (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 of the yeast 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), -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 shock, inflammatory cytokines, lipopolysaccharides (LPS), ultraviolet light, and growth factors.

MKK3 and SEK activate p38 MAP kinase by phosphorylation 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, 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. P38 was also shown to correlate with outcome of glioblastoma - 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. 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 (FSHD) on the basis of p38 inhibition inhibiting the effects of DUX4.