Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Signals emanating from many cell-surface receptors and environmental cues converge on mitogen-activated protein kinases (MAPKs), which in turn phosphorylate and activate various transcription factors and other molecular effectors. Members of the p38 MAPK family, which respond to pro-inflammatory cytokines and cellular stresses, are typically activated by serial phosphorylation and activation of upstream kinases (the MAPK cascade). In this Review, I highlight the recent studies that indicate that p38-subfamily members can also be activated by non-canonical mechanisms, at least one of which seems to have an important role in antigen-receptor-activated T cells. These alternative pathways might have particular relevance for cells that participate in immune and inflammatory responses.
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Acknowledgements
I am grateful to P. R. Mittelstadt and R. Bosselut for helpful comments on this manuscript. The Laboratory of Immune Cell Biology is supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute, USA.
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Glossary
- Serine/threonine kinases
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Enzymes that catalyse the phosphorylation of serine or threonine residues in proteins.
- Dual-specificity kinases
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Enzymes that catalyse the phosphorylation of tyrosine, and serine or threonine residues in proteins.
- Collagen-induced arthritis
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(CIA). A model of rheumatoid arthritis. CIA develops in susceptible rodents and primates after immunization with cartilage-derived type II collagen.
- Endotoxin-induced septic shock
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Results from uncontrolled production of pro-inflammatory cytokines owing to bacterial overload. Death might result from multi-organ failure.
- Tetraploid rescue
-
A complementation technique for producing a normal placenta that supports the development of mutant embryos. Briefly, two-cell embryos are fused to create tetraploid cells, which can contribute to all extraembryonic tissues but not to the embryo itself. The tetraploid cells are aggregated with diploid embryonic stem cells or early embryos and implanted into pseudopregnant recipients.
- RAG-deficient blastocyst complementation method
-
A gene-targeting technique used for the genetic analysis of lymphocytes. Complementation of recombination-activating gene 2 (RAG2)-deficient blastocysts (which cannot produce mature T or B cells) with embryonic stem cells that have a mutation in the gene of interest creates chimaeras that have genetically altered T and B cells.
- RNA interference
-
The use of double-stranded RNAs with sequences that precisely match a given gene, to knock-down the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.
- Vβ8.1-transgenic mice
-
Mice expressing a T-cell receptor (TCR) β-chain of which the variable region is encoded by the 8.1 gene segment. Vβ8.1 binds several superantigens, which results in TCR signalling.
- Superantigen
-
A microbial protein that binds to and activates all T cells that express a particular set of TCR Vβ-chains.
- Aneuploidy
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The occurrence of one or more extra or missing chromosomes, which leads to an unbalanced chromosome complement.
- Gene amplification
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The production of multiple copies of a gene or genes.
- Lupus-like autoimmunity
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An autoimmune disease similar to systemic lupus erythematosus in humans.
- SRC-family kinases
-
A class of cytoplasmic protein tyrosine kinases involved in the initiation of receptor signalling. They include LCK, FYN, LYN, HCK, BLK, C-YES, C-SRC, C-FGR and YRK.
- High-pressure liquid chromatography
-
A rapid variant of column chromatography used for high-resolution separation of molecules of low-to-moderate molecular weight.
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Ashwell, J. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 6, 532–540 (2006). https://doi.org/10.1038/nri1865
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DOI: https://doi.org/10.1038/nri1865
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