activated TAK1 mediates p38 MAPK activation

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Homo sapiens
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p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases.

The p38 MAPK-dependent signaling cascade is activated by pro-inflammatory or stressful stimuli such as ultraviolet radiation, oxidative injury, heat shock, cytokines, and other pro-inflammatory stimuli. p38 MAPK exists as four isoforms (alpha, beta, gamma, and delta). Of these, p38alpha and p38beta are ubiquitously expressed while p38gamma and p38delta are differentially expressed depending on tissue type. Each isoform is activated by upstream kinases including MAP kinase kinases (MKK) 3, 4, and 6, which in turn are phosphorylated by activated TAK1 at the typical Ser-Xaa-Ala-Xaa-Thr motif in their activation loops.

Once p38 MAPK is phosphorylated it activates numerous downstream substrates, including MAPK-activated protein kinase-2 and 3 (MAPKAPK-2 or 3) and mitogen and stress-activated kinase-1/2 (MSK1/2). MAPKAPK-2/3 and MSK1/2 function to phosphorylate heat shock protein 27 (HSP27) and cAMP-response element binding protein transcriptional factor, respectively. Other transcription factors, including activating transcription factor 2, Elk, CHOP/GADD153, and myocyte enhancer factor 2, are known to be regulated by these kinases.

Literature References
PubMed ID Title Journal Year
15837794 Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes

Kracht, M, Wolter, S, Resch, K, Dittrich-Breiholz, O, Wirth, D, Thiefes, A, Mushinski, JF, Luckow, B, Schneider, H, Graue, N, Dörrie, A, Hoffmann, E

J Biol Chem 2005
8533096 Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction

Nishida, E, Shibuya, H, Shirakabe, K, Ueno, N, Oishi, I, Matsumoto, K, Yamaguchi, K, Irie, K, Taniguchi, T

Science 1995
26988982 IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells

Liu, Y, Wang, SS, Li, JK, Nie, L, Wang, X, Zhao, YP, Zhao, H, Cheng, L, Zhang, YQ

J Transl Med 2016
10878576 p38 MAPK signalling cascades: ancient roles and new functions

Martin-Blanco, E

Bioessays 2000
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