p38 MAPK Signaling

p38 MAPKs (α, β, γ, and δ) are members of the MAPK family that are activated by a variety of environmental stresses and inflammatory cytokines. As with other MAPK cascades, the membrane-proximal component is a MAPKKK, typically a MEKK or a mixed lineage kinase (MLK). The MAPKKK phosphorylates and activates MKK3/6, the p38 MAPK kinases. MKK3/6 can also be activated directly by ASK1, which is stimulated by apoptotic stimuli. p38 MAPK is involved in regulation of HSP27, MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and several transcription factors including ATF-2, Stat1, the Max/Myc complex, MEF-2, Elk-1, and indirectly CREB via activation of MSK1.

Selected Reviews:

• Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA (2009) p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med 15(8), 369–79.
• Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem. J. 429(3), 403–17.
• del Barco Barrantes I, Nebreda AR (2012) Roles of p38 MAPKs in invasion and metastasis. Biochem. Soc. Trans. 40(1), 79–84.
• Huang G, Shi LZ, Chi H (2009) Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. Cytokine 48(3), 161–9.
• Kostenko S, Dumitriu G, Lægreid KJ, Moens U (2011) Physiological roles of mitogen-activated-protein-kinase-activated p38-regulated/activated protein kinase. World J Biol Chem 2(5), 73–89.
• Shiryaev A, Moens U (2010) Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: ménage à trois or ménage à quatre? Cell. Signal. 22(8), 1185–92.

We would like to thank Prof. John Blenis, Harvard Medical School, Boston, MA, for contributing to this diagram.

created January 2003

revised October 2012