The many paths to p38 mitogen-activated protein kinase activation in the immune system

Abstract

Three p38 mitogen-activated protein kinase (MAPK)-family members (p38α, p38β and p38δ) are expressed by immune and inflammatory cells, and are activated by extracellular stimuli such as stress (for example, hypoxia, reactive oxygen species and changes in osmolarity) and pro-inflammatory cytokines (for example, interleukin-1, tumour-necrosis factor and transforming growth factor-β). Although similar in many ways, p38-family members have different tissue distributions and fine specificity for substrates. Studies using specific chemical inhibitors and gene targeting of activators upstream of p38α and p38β have revealed important roles for these kinases in both the production of, and response to, pro-inflammatory stimuli. Little is known about the biological role of p38δ. In the MAPK cascade, p38-family members are activated by serial phosphorylation of upstream kinases that culminate in p38 dual phosphorylation of the Thr-Gly-Tyr motif in the activation loop. p38α specifically binds to and is activated by TAK1-binding protein 1 (TAB1). A hallmark of this activation pathway is p38α autophosphorylation of its own Thr-Gly-Tyr motif. In T cells, T-cell-receptor-induced activation of ζ-chain-associated protein kinase of 70 kDa (ZAP70) leads to p38α/p38β phosphorylation of Tyr323, which induces robust autophosphorylation of the Thr-Gly-Tyr motif and increased activity towards third-party substrates. The activity of spontaneously Tyr323-phosphorylated p38α/p38β is normally regulated by growth arrest and DNA-damage-inducible 45α (GADD45α), and in its absence mice develop T-cell hyperproliferation and autoimmunity.