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.
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]
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]
Inhibitorsedit
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.
^Cosgrove BD, Gilbert PM, Porpiglia E, Mourkioti F, Lee SP, Corbel SY, Llewellyn ME, Delp SL, Blau HM (2014). "Rejuvenation of the muscle stem cell population restores strength to injured aged muscles". Nature Medicine. 20 (3): 255–64. doi:10.1038/nm.3464. PMC3949152. PMID 24531378.
^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. PMC5003838. 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. Bibcode:1994Sci...265..808H. doi:10.1126/science.7914033. PMID 7914033.
^ She QB, Chen N, Dong Z (July 2000). "ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation". Journal of Biological Chemistry. 275 (27): 20444–20449. doi:10.1074/jbc.M001020200. PMID 10781582.
^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 Letters. 583 (12): 1933–8. doi:10.1016/j.febslet.2009.04.039. PMC4798241. PMID 19416727.
^Dusik V, Senthilan PR, Mentzel B, Hartlieb H, Wülbeck C, Yoshii T, Raabe T, Helfrich-Förster C (2014). "The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock". PLOS Genetics. 10 (8): e1004565. doi:10.1371/journal.pgen.1004565. PMC4140665. PMID 25144774.
^Anerillas C, Abdelmohsen K, Gorospe M (2020). "Regulation of senescence traits by MAPKs". GeroScience. 42 (2): 397–408. doi:10.1007/s11357-020-00183-3. PMC7205942. PMID 32300964.
^Yan SD, Bierhaus A, Nawroth PP, Stern DM (2009). "RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation?". Journal of Alzheimer's Disease. 16 (4): 833–43. doi:10.3233/JAD-2009-1030. PMC3726270. PMID 19387116.
^Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ (July 2011). "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. doi:10.1186/1742-2094-8-79. PMC3142505. PMID 21733175.
^Zhou Z, Bachstetter AD, Späni CB, Roy SM, Watterson DM, Van Eldik LJ (April 2017). "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. doi:10.1186/s12974-017-0845-2. PMC5382362. PMID 28381303.
^Wei S, Siegal GP (2008). "Mechanisms modulating inflammatory osteolysis: a review with insights into therapeutic targets". Pathology, Research and Practice. 204 (10): 695–706. doi:10.1016/j.prp.2008.07.002. PMC3747958. PMID 18757139.
^Barnes PJ (July 2016). "Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease". Pharmacological Reviews. 68 (3): 788–815. doi:10.1124/pr.116.012518. PMID 27363440.
^Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y (June 2016). "The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy". International Journal of Molecular Sciences. 17 (7): E1037. doi:10.3390/ijms17071037. PMC4964413. PMID 27376265.
^Segalés J, Perdiguero E, Muñoz-Cánoves P (August 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. PMC5003838. PMID 27626031.
^Lang E, Bissinger R, Qadri SM, Lang F (October 2017). "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. doi:10.1002/ijc.30800. PMID 28542880.
^Bonney EA (May 2017). "Mapping out p38MAPK". American Journal of Reproductive Immunology. 77 (5): e12652. doi:10.1111/aji.12652. PMC5527295. PMID 28194826.
^Vlahopoulos SA (August 2017). "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. doi:10.20892/j.issn.2095-3941.2017.0029. PMC5570602. PMID 28884042.
^Ben-Hamo R, Efroni S (2013-04-11). "hsa-miR-9 and drug control over the P38 network as driving disease outcome in GBM patients". Systems Biomedicine. 1 (2): 76–83. doi:10.4161/sysb.25815. ISSN 2162-8130.
^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". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 610–9. doi:10.1124/jpet.108.139006. PMID 18776065. S2CID 7079672.
^"Novel p38 Inhibitor Shows Promise as Anti-Inflammatory Treatment for Patients With COPD". 2010.
^Mellion M, Ronco L, Thompson D, Hage M, Brooks S, van Brummelen E, Pagan L, Badrising U, Van Engelen B, Groeneveld G, Cadavid D (October 2019). "O.25Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement". Neuromuscular Disorders. 29: S123. doi:10.1016/j.nmd.2019.06.308.
External linksedit
p38+Mitogen-Activated+Protein+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
mitogen, activated, protein, kinases, main, article, mitogen, activated, protein, kinase, class, mitogen, activated, protein, kinases, mapks, that, responsive, stress, stimuli, such, cytokines, ultraviolet, irradiation, heat, shock, osmotic, shock, involved, c. Main article Mitogen activated protein kinase 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 mitogen activated protein kinase 11IdentifiersSymbolMAPK11Alt symbolsPRKM11NCBI gene5600HGNC6873OMIM602898RefSeqNM 002751UniProtQ15759Other dataEC number2 7 11 24LocusChr 22 q13 33Search forStructuresSwiss modelDomainsInterPromitogen activated protein kinase 12IdentifiersSymbolMAPK12Alt symbolsSAPK3NCBI gene6300HGNC6874OMIM602399RefSeqNM 002969UniProtP53778Other dataEC number2 7 11 24LocusChr 22 q13 3Search forStructuresSwiss modelDomainsInterPromitogen activated protein kinase 13IdentifiersSymbolMAPK13Alt symbolsPRKM13NCBI gene5603HGNC6875OMIM602899RefSeqNM 002754UniProtO15264Other dataEC number2 7 11 24LocusChr 6 p21Search forStructuresSwiss modelDomainsInterPromitogen activated protein kinase 14IdentifiersSymbolMAPK14Alt symbolsCSPB1 CSBP1 CSBP2NCBI gene1432HGNC6876OMIM600289RefSeqNM 001315UniProtQ16539Other dataEC number2 7 11 24LocusChr 6 p21 3 21 2Search forStructuresSwiss modelDomainsInterProp38 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 a MAPK14 b MAPK11 g MAPK12 ERK6 and d 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 Contents 1 Clinical significance 2 Inhibitors 3 References 4 External linksClinical significance editOxidative 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 kB 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 kB 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 editp38 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 References edit Cosgrove BD Gilbert PM Porpiglia E Mourkioti F Lee SP Corbel SY Llewellyn ME Delp SL Blau HM 2014 Rejuvenation of the muscle stem cell population restores strength to injured aged muscles Nature Medicine 20 3 255 64 doi 10 1038 nm 3464 PMC 3949152 PMID 24531378 Segales J Perdiguero E Munoz Canoves 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 Bibcode 1994Sci 265 808H doi 10 1126 science 7914033 PMID 7914033 She QB Chen N Dong Z July 2000 ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation Journal of Biological Chemistry 275 27 20444 20449 doi 10 1074 jbc M001020200 PMID 10781582 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 Letters 583 12 1933 8 doi 10 1016 j febslet 2009 04 039 PMC 4798241 PMID 19416727 Dusik V Senthilan PR Mentzel B Hartlieb H Wulbeck C Yoshii T Raabe T Helfrich Forster C 2014 The MAP Kinase p38 Is Part of Drosophila melanogaster s Circadian Clock PLOS Genetics 10 8 e1004565 doi 10 1371 journal pgen 1004565 PMC 4140665 PMID 25144774 Anerillas C Abdelmohsen K Gorospe M 2020 Regulation of senescence traits by MAPKs GeroScience 42 2 397 408 doi 10 1007 s11357 020 00183 3 PMC 7205942 PMID 32300964 Yan SD Bierhaus A Nawroth PP Stern DM 2009 RAGE and Alzheimer s disease a progression factor for amyloid beta induced cellular perturbation Journal of Alzheimer s Disease 16 4 833 43 doi 10 3233 JAD 2009 1030 PMC 3726270 PMID 19387116 Bachstetter AD Xing B de Almeida L Dimayuga ER Watterson DM Van Eldik LJ July 2011 Microglial p38a MAPK is a key regulator of proinflammatory cytokine up regulation induced by toll like receptor TLR ligands or beta amyloid Ab Journal of Neuroinflammation 8 79 doi 10 1186 1742 2094 8 79 PMC 3142505 PMID 21733175 Zhou Z Bachstetter AD Spani CB Roy SM Watterson DM Van Eldik LJ April 2017 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 doi 10 1186 s12974 017 0845 2 PMC 5382362 PMID 28381303 Wei S Siegal GP 2008 Mechanisms modulating inflammatory osteolysis a review with insights into therapeutic targets Pathology Research and Practice 204 10 695 706 doi 10 1016 j prp 2008 07 002 PMC 3747958 PMID 18757139 Barnes PJ July 2016 Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease Pharmacological Reviews 68 3 788 815 doi 10 1124 pr 116 012518 PMID 27363440 Wang S Ding L Ji H Xu Z Liu Q Zheng Y June 2016 The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy International Journal of Molecular Sciences 17 7 E1037 doi 10 3390 ijms17071037 PMC 4964413 PMID 27376265 Segales J Perdiguero E Munoz Canoves P August 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 Lang E Bissinger R Qadri SM Lang F October 2017 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 doi 10 1002 ijc 30800 PMID 28542880 Bonney EA May 2017 Mapping out p38MAPK American Journal of Reproductive Immunology 77 5 e12652 doi 10 1111 aji 12652 PMC 5527295 PMID 28194826 Vlahopoulos SA August 2017 Aberrant control of NF kB in cancer permits transcriptional and phenotypic plasticity to curtail dependence on host tissue molecular mode Cancer Biology amp Medicine 14 3 254 270 doi 10 20892 j issn 2095 3941 2017 0029 PMC 5570602 PMID 28884042 Ben Hamo R Efroni S 2013 04 11 hsa miR 9 and drug control over the P38 network as driving disease outcome in GBM patients Systems Biomedicine 1 2 76 83 doi 10 4161 sysb 25815 ISSN 2162 8130 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 The Journal of Pharmacology and Experimental Therapeutics 327 3 610 9 doi 10 1124 jpet 108 139006 PMID 18776065 S2CID 7079672 Novel p38 Inhibitor Shows Promise as Anti Inflammatory Treatment for Patients With COPD 2010 Mellion M Ronco L Thompson D Hage M Brooks S van Brummelen E Pagan L Badrising U Van Engelen B Groeneveld G Cadavid D October 2019 O 25Phase 1 clinical trial of losmapimod in FSHD safety tolerability and target engagement Neuromuscular Disorders 29 S123 doi 10 1016 j nmd 2019 06 308 External links editp38 Mitogen Activated Protein Kinases at the U S National Library of Medicine Medical Subject Headings MeSH P38mapkPathway p38 Signaling Pathway MAP Kinase Resource Archived 2021 04 15 at the Wayback Machine p38 MAPK Pathway Portal nbsp Biology This EC 2 7 enzyme related article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title P38 mitogen activated protein kinases amp oldid 1198690274, wikipedia, wiki, book, books, library,
