| Description: |
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 []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual 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 []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. 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 [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the non-receptor tyrosine kinases SYK and ZAP-70 [, , ]:SYK is a positive effector of BCR-stimulated responses. It couples the B-cell antigen receptor (BCR) to the mobilisation of calcium ion, either through a phosphoinositide 3-kinase-dependent pathway (when not phosphorylated on tyrosines of the linker region), or through a phospholipase C-gamma-dependent pathway (when phosphorylated on Tyr-342 and Tyr-346). Therefore, the differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion [, ].ZAP70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production. Isoform 1 of ZAP70 induces TCR-mediated signal transduction, isoform 2 does not [, ]. |
