The p38MAPKsignalling pathway

Schematic representation of the p38MAPKsignalling pathway. A variety of extracellular signals, such as cellular stresses and pro-inflammatory cytokines, can activate the p38MAPKpathway. These lead to the initiation of a three-tiered MAPK phosphorylation cascade in which MAPKKKs phosphorylate the p38MAPK-specific MAPKKs MKK3, MKK4 or MKK6. These subsequently phosphorylate four isoforms of p38MAPK (α, β, δ and γ) and three alternatively spliced variants of p38α and p38β: Mxi2, Exip (both p38α variants, dark blue boxes) and p38β2 (p38β variant, pale blue boxes). Of note, only ASK1 can activate MKK4, which specifically activates p38α, and MKK6 preferentially phosphorylates p38β. It is not known which MKKs phosphorylate the splice variants (dashed line). p38MAPK substrates can be isoform-specific or common to all isoforms. Substrates are coloured according to function: protein kinases (purple), transcription factors (orange) and cytosolic and nuclear proteins (green). Phosphorylated substrates go on to elicit varied biological responses that include inflammation, apoptosis, proliferation, cell-cycle regulation and differentiation. Dashed lines indicate potential links yet to be confirmed. Abbreviations: ASK1, Apoptosis signalling kinase 1; CHOP, CCAAT/enhancer-binding protein-homologous protein; GS, Glycogen synthase; MEKK, MEK kinase; MNK, MAPK interacting kinase; PRAK, p38-regulated/activated protein kinase; p75NTR: p75 neurotrophin; STAT1, signal transducer and activator of transcription 1; TAK1, transforming growth factor activated kinase 1; TAO, thousand and one amino acid kinase.

Publication

p38MAPK: stress responses from molecular mechanisms to therapeutics. () Lydia R. Coulthard, et al. Trends Mol Med. ;15(8):369-379. Figure: F1. All organisms Mus musculus Homo sapiens Rattus norvegicus Canis lupus familiaris Drosophila melanogaster

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