P38 mitogen-activated protein kinases explained

See main article: Mitogen-activated protein kinase.

mitogen-activated protein kinase 11
Hgncid:6873
Symbol:MAPK11
Altsymbols:PRKM11
Entrezgene:5600
Omim:602898
Refseq:NM_002751
Uniprot:Q15759
Ecnumber:2.7.11.24
Chromosome:22
Arm:q
Band:13.33
mitogen-activated protein kinase 12
Hgncid:6874
Symbol:MAPK12
Altsymbols:SAPK3
Entrezgene:6300
Omim:602399
Refseq:NM_002969
Uniprot:P53778
Ecnumber:2.7.11.24
Chromosome:22
Arm:q
Band:13.3
mitogen-activated protein kinase 13
Hgncid:6875
Symbol:MAPK13
Altsymbols:PRKM13
Entrezgene:5603
Omim:602899
Refseq:NM_002754
Uniprot:O15264
Ecnumber:2.7.11.24
Chromosome:6
Arm:p
Band:21
mitogen-activated protein kinase 14
Hgncid:6876
Symbol:MAPK14
Altsymbols:CSPB1, CSBP1, CSBP2
Entrezgene:1432
Omim:600289
Refseq:NM_001315
Uniprot:Q16539
Ecnumber:2.7.11.24
Chromosome:6
Arm:p
Band:21.3-21.2

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.[1] [2]

p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue of the yeast Hog1p MAP kinase,[3] 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.[4] p38 also has been shown to phosphorylate post-transcriptional regulating factors like TTP,[5] and in fruit flies it plays a role in regulating the circadian clock.[6]

Clinical significance

Oxidative stress is the most powerfully specific stress activating p38 MAPK.[7] Abnormal activity (higher or lower than physiological) of p38 has been implicated in pathological stresses in several tissues, that include neuronal,[8] [9] [10] bone,[11] lung,[12] cardiac and skeletal muscle,[13] [14] red blood cells,[15] and fetal tissues.[16] 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.[17] P38 was also shown to correlate with outcome of glioblastoma - higher pathway activity is associated with low survival.[18]

Inhibitors

p38 inhibitors are being sought for possible therapeutic effect on autoimmune diseases and inflammatory processes,[19] e.g. pamapimod.[20] Some have started clinical trials, e.g. PH-797804 for COPD.[21] 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.[22]

External links

Notes and References

  1. Cosgrove BD, Gilbert PM, Porpiglia E, Mourkioti F, Lee SP, Corbel SY, Llewellyn ME, Delp SL, Blau HM . Rejuvenation of the muscle stem cell population restores strength to injured aged muscles . Nature Medicine . 20 . 255–64 . 2014 . 3 . 24531378 . 3949152 . 10.1038/nm.3464 .
  2. Segalés J, Perdiguero E, Muñoz-Cánoves P . Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway . Frontiers in Cell and Developmental Biology . 4 . 91 . 2016 . 27626031 . 5003838 . 10.3389/fcell.2016.00091 . free .
  3. Han J, Lee JD, Bibbs L, Ulevitch RJ . A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells . Science . 265 . 5173 . 808–11 . August 1994 . 7914033 . 10.1126/science.7914033 . 1994Sci...265..808H .
  4. She QB, Chen N, Dong Z . ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation . Journal of Biological Chemistry . 275 . 27 . 20444–20449 . July 2000 . 10781582 . 10.1074/jbc.M001020200 . free .
  5. Tudor C, Marchese FP, Hitti E, Aubareda A, Rawlinson L, Gaestel M, Blackshear PJ, Clark AR, Saklatvala J, Dean JL . The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages . FEBS Letters . 583 . 12 . 1933–8 . June 2009 . 19416727 . 4798241 . 10.1016/j.febslet.2009.04.039 .
  6. Dusik V, Senthilan PR, Mentzel B, Hartlieb H, Wülbeck C, Yoshii T, Raabe T, Helfrich-Förster C . The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock . PLOS Genetics . 10 . 8 . e1004565 . 2014 . 25144774 . 10.1371/journal.pgen.1004565 . 4140665 . free .
  7. Anerillas C, Abdelmohsen K, Gorospe M . Regulation of senescence traits by MAPKs . . 42 . 2 . 397–408 . 2020 . 10.1007/s11357-020-00183-3 . 7205942 . 32300964.
  8. Yan SD, Bierhaus A, Nawroth PP, Stern DM . RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation? . Journal of Alzheimer's Disease . 16 . 4 . 833–43 . 2009 . 19387116 . 3726270 . 10.3233/JAD-2009-1030 .
  9. Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ . Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ) . Journal of Neuroinflammation . 8 . 79 . July 2011 . 21733175 . 3142505 . 10.1186/1742-2094-8-79 . free .
  10. Zhou Z, Bachstetter AD, Späni CB, Roy SM, Watterson DM, Van Eldik LJ . Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes . Journal of Neuroinflammation . 14 . 1 . 75 . April 2017 . 28381303 . 5382362 . 10.1186/s12974-017-0845-2 . free .
  11. Wei S, Siegal GP . Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic targets . Pathology, Research and Practice . 204 . 10 . 695–706 . 2008 . 18757139 . 3747958 . 10.1016/j.prp.2008.07.002 .
  12. Barnes PJ . Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease . Pharmacological Reviews . 68 . 3 . 788–815 . July 2016 . 27363440 . 10.1124/pr.116.012518 . free .
  13. Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y . The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy . International Journal of Molecular Sciences . 17 . 7 . E1037 . June 2016 . 27376265 . 4964413 . 10.3390/ijms17071037 . free .
  14. Segalés J, Perdiguero E, Muñoz-Cánoves P . Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway . Frontiers in Cell and Developmental Biology . 4 . 91 . August 2016 . 27626031 . 5003838 . 10.3389/fcell.2016.00091 . free .
  15. Lang E, Bissinger R, Qadri SM, Lang F . Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia . International Journal of Cancer . 141 . 8 . 1522–1528 . October 2017 . 28542880 . 10.1002/ijc.30800 . free .
  16. Bonney EA . Mapping out p38MAPK . American Journal of Reproductive Immunology . 77 . 5 . May 2017 . e12652 . 28194826 . 5527295 . 10.1111/aji.12652 .
  17. Vlahopoulos SA . Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode . Cancer Biology & Medicine . 14 . 3 . 254–270 . August 2017 . 28884042 . 5570602 . 10.20892/j.issn.2095-3941.2017.0029 .
  18. Ben-Hamo . Rotem . Efroni . Sol . 2013-04-11 . hsa-miR-9 and drug control over the P38 network as driving disease outcome in GBM patients . Systems Biomedicine . en . 1 . 2 . 76–83 . 10.4161/sysb.25815 . 2162-8130. free .
  19. Goldstein DM, Gabriel T . Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development . Current Topics in Medicinal Chemistry . 5 . 10 . 1017–29 . 2005 . 16178744 . 10.2174/1568026054985939 .
  20. Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leaffer D, Kim YN, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, Wong BR . Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity . The Journal of Pharmacology and Experimental Therapeutics . 327 . 3 . 610–9 . December 2008 . 18776065 . 10.1124/jpet.108.139006 . 7079672 .
  21. Web site: Novel p38 Inhibitor Shows Promise as Anti-Inflammatory Treatment for Patients With COPD . 2010 .
  22. Mellion . M. . Ronco . L. . Thompson . D. . Hage . M. . Brooks . S. . van Brummelen . E. . Pagan . L. . Badrising . U. . Van Engelen . B. . Groeneveld . G. . Cadavid . D. . O.25Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement . Neuromuscular Disorders . October 2019 . 29 . S123 . 10.1016/j.nmd.2019.06.308. free .

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