p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue of the yeastHog1p MAP kinase,[3] which participates in a signaling cascade controlling cellular responses to cytokines and stress.
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.
^Goldstein DM, Gabriel T (2005). "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. doi:10.2174/1568026054985939. PMID16178744.
^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 (December 2008). "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. doi:10.1124/jpet.108.139006. PMID18776065. S2CID7079672.
