p38(MAPK): stress responses from molecular mechanisms to therapeutics

Abstract

The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discuss how the p38(MAPK) pathway might be best exploited for the development of more effective therapeutics with minimal side effects in a range of specific disease settings.

Figure 1

Schematic representation of the p38^MAPK signalling pathway. A variety of extracellular signals, such as cellular stresses and pro-inflammatory cytokines, can activate the p38^MAPK pathway. These lead to the initiation of a three-tiered MAPK phosphorylation cascade in which MAPKKKs phosphorylate the p38^MAPK-specific MAPKKs MKK3, MKK4 or MKK6. These subsequently phosphorylate four isoforms of p38^MAPK (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). p38^MAPK 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; p75^NTR: p75 neurotrophin; STAT1, signal transducer and activator of transcription 1; TAK1, transforming growth factor activated kinase 1; TAO, thousand and one amino acid kinase.

Figure 2

p38^MAPK activation and inhibition. (a) p38^MAPK is activated in multiple steps. ATP is required for phosphorylation of the TGY motif on the activation loop. Once this has occurred, there is a conformational change in the kinase, exposing a binding site for a substrate. (b) Classical pyridinyl imidazole inhibitors (e.g. SB203580) are similar in shape to ATP molecules and compete for the ATP-binding site. Once the inhibitor is bound, ATP is blocked and phosphorylation of the TGY motif does not occur, leaving p38^MAPK inactive. (c) Newer p38^MAPK inhibitors (e.g. BIRB796) can act on distinct sites on the enzyme, which then cause a conformational change in the ATP-binding site, again blocking ATP and preventing activation.