activated TAK1 mediates p38 MAPK activation Authored: Shamovsky, V, 2009-12-16 Edited: Shamovsky, V, 2010-02-27 GENE ONTOLOGYGO:0000187 Pubmed10878576 Pubmed15837794 Pubmed8533096 Pubmed8622669 Reactome Database ID Release 43450302 Reactome, http://www.reactome.org ReactomeREACT_21399 Reviewed: Gillespie, ME, 2010-02-27 p38 mitogen-activated protein kinase (MAPK) belongs to a highly conserved family of serine/threonine protein kinases. <p>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.<p>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. PathwayStep3445 PathwayStep3444 PathwayStep3447 PathwayStep3446 PathwayStep3448 Nuclear export of human p38 MAPK mediated by its substrate MAPKAPK2 or 3 activated human MKK3/MKK6 phosphorylates p38 MAPK complexed with MAPKAPK2 or MAPKAPK3 activated human TAK1 phosphorylates MKK3/MKK6 phosphorylated MKK3/MKK6 migrates to nucleus