p38 mitogen activated protein family of kinases (p38 MAPK) are activated by a diverse array of stress stimuli that include inflammatory cytokines, death ligands (e.g. TNF), transforming growth factor (TGF)-β -related polypeptides and environmental factors like oxidative stress and UV radiation. Response to stress by activated p38 MAPKs culminates in enhanced transcriptional activity, protein synthesis and cell death.Like all MAPKs, p38MAPKs are members of a 3 tiered kinase module. Thus a MAPK kinase (MKK) activates p38 MAPK, while a MAPKK kinase (MKKK) activates the MKK. The p38 module consists of several MAPKKKs, including apoptosis signal regulating kinase 1(ASK1) and TGF-beta activated kinase 1 (TAK1); the MAPKKs including MKK3, MKK4 and MKK6 and the four known p38 isoforms (α,β,γ and δ). The MAPKKs are selective about which p38 MAPK isoform they will phosphorylate and activate.
The activation of p38MAPKs results in the down stream phosphorylation of several protein kinases termed MAPK-activated protein kinases (MKs). These include the MAPK-interacting kinases (MNKs), the mitogen- and stress-activated kinases (MSKs) and MAPK-activated protein kinases 2 /3 (MAPKAP-K2 and -3). The MKs represent an additional amplification step in the p38 MAPK catalytic cascades. p38 MAPK is known to translocate to the nucleus where it phosphorylates transcription factors like activating transcription factor (ATF1 and -2), myocyte-specific enhancer-binding factor -2 (MEF2), Elk-1 and cAMP regulatory element binding protein (CREB). Phosphorylation of some transcription factors is mediated via p38 MAPK activation of MSKs and MAPKAPs. The activated trans factors trigger transcription of several stress response genes e.g. those responsible for cytokine production and apoptosis.
This pathway highlights the important components of p38 MAPK activation.