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].

Eukaryotic serine-threonine mitogen-activated protein (MAP) kinases are key regulators of cellular signal transduction systems and are conserved from Saccharomyces cerevisiae (Baker's yeast) to human beings. MAPK pathways are signalling cascades differentially regulated by growth factors, mitogens, hormones and stress which mediate cell growth, differentiation and survival. MAPK activity is regulated through a (usually) three-tiered cascade composed of a MAPK, a MAPK kinase (MAPKK, MEK) and a MAPK kinase kinase (MAPKK, MEKK). Substrates for the MAPKs include other kinases and transcription factors [6].

Mammals express at least four distinctly related groups of MAPKs, extracellularly-regulated kinases (ERKs), c-jun N-terminal kinases (JNKs), p38 proteins and ERK5. Plant MAPK pathways have attracted increasing interest, resulting in the isolation of a large number of different components of MAPK cascades. MAPKs play important roles in the signalling of most plant hormones and in developmental processes [7]. In the budding yeast S. cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK)activation pathways are known, regulating mating, cell integrity and osmosity [8].

Enzymes in this family are characterised by two domains separated by a deep channel where potential substrates might bind. The N-terminal domain creates a binding pocket for the adenine ring of ATP, and the C-terminal domain contains the catalytic base, magnesium binding sites and phosphorylation lip [9]. Almost all MAPKs possess a conserved TXY motif in which both the threonine andtyrosine residues are phosphorylated during activation of the enzyme byupstream dual-specificity MAP kinase kinases (MAPKKs).

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. Mammalian MAP kinase signalling cascades. Nature 410, 37-40
7. Mitogen-activated protein (MAP] kinase pathways in plants: versatile signaling tools. Int. Rev. Cytol. 201, 209-75
8. Dynamics and organization of MAP kinase signal pathways. Mol. Reprod. Dev. 42, 477-85
9. Crystal structure of p38 mitogen-activated protein kinase. J. Biol. Chem. 271, 27696-700

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible proc
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