p38 mitogen-activated protein kinases
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]
p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue of the yeast Hog1p MAP kinase,[2] 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.
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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 and MEF2. p38 also has been shown to phosphorylate post-transcriptional regulating factors like TTP.[3]
P38 inhibitors
P38 inhibitors are being sought for possible therapeutic effect on autoimmune diseases and inflammatory processes,[4] e.g. pamapimod.[5] Some have started clinical trials, e.g. PH-797804 for COPD.[6] Other p38 inhibitors include BIRB 796, VX-702, SB 239063, SB202190, SCIO 469, and BMS 582949.
References
- ↑ Segalés J, Perdiguero E, Muñoz-Cánoves P (2016). "Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway". FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY. 4: 91. doi:10.3389/fcell.2016.00091. PMC 5003838
. PMID 27626031. - ↑ Han J, Lee JD, Bibbs L, Ulevitch RJ (August 1994). "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells". Science. 265 (5173): 808–11. doi:10.1126/science.7914033. PMID 7914033.
- ↑ Tudor C, Marchese FP, Hitti E, Aubareda A, Rawlinson L, Gaestel M, Blackshear PJ, Clark AR, Saklatvala J, Dean JL (June 2009). "The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages". FEBS Lett. 583 (12): 1933–8. doi:10.1016/j.febslet.2009.04.039. PMID 19416727.
- ↑ 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. PMID 16178744.
- ↑ 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". J. Pharmacol. Exp. Ther. 327 (3): 610–9. doi:10.1124/jpet.108.139006. PMID 18776065.
- ↑ "Novel p38 Inhibitor Shows Promise as Anti-Inflammatory Treatment for Patients With COPD". 2010.
External links
- p38 Mitogen-Activated Protein Kinases at the US National Library of Medicine Medical Subject Headings (MeSH)
- P38mapkPathway
- p38 Signaling Pathway
- MAP Kinase Resource
- p38 MAPK Pathway