InterPro domain: IPR008352

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [ 1 ]:

• Serine/threonine-protein kinases
• Tyrosine-protein kinases
• Dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human [ 2 ]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [ 3 ]. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [ 4 ], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [ 5 ].

MAP (Mitogen Activated Protein) kinases participate in kinase cascades,whereby at least 3 protein kinases act in series, culminating in activationof MAP kinase [ 6 ]. MAP kinases are activated by dual phosphorylationon both tyrosine and threonine residues of a conserved TXY motif.

p38 proteins belong to the MAP kinase family and were discovered in 3different contexts independently: first, as tyrosine phosphoproteins foundin extracts of cells treated with inflammatory cytokines; second, astargets of a pyrinidyl imidazole drug that blocks production of TNFalpha; and third, as reactivating kinases for MAP kinase-activated protein(MAPKAP) [ 7 ]. The proteins are activated by cytokines, hormones, GPCRs,osmotic shock, heat shock and other stresses [ 7 ].

1. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42-52
2. The protein kinase complement of the human genome. Science 298, 1912-34
3. Evolution of protein kinase signaling from yeast to man. Trends Biochem. Sci. 27, 514-20
4. High-throughput structural biology in drug discovery: protein kinases. Curr. Pharm. Des. 10, 1069-82
5. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screen. 7, 453-72
6. The stress-activated protein kinase pathways. Cell. Mol. Life Sci. 55, 1230-54
7. In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol. Chem. 383, 1519-36