Tyrosine-protein kinase, receptor class II, conserved site (Tyr_kinase_rcpt_2_CS)
Type: Conserved_site

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 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 . 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 .

A number of growth factors stimulate mitogenesis by interacting with a family of cell surface receptors which possess an intrinsic, ligand-sensitive, protein tyrosine kinase activity . These receptor tyrosine kinases (RTK) all share the same topology: an extracellular ligand-binding domain, a single transmembrane region and a cytoplasmic kinase domain. However they can be classified into at least five groups. The prototype for class II RTK's is the insulin receptor, a heterotetramer of two alpha and two beta chains linked by disulphide bonds. The alpha and beta chains are cleavage products of a precursor molecule. The alpha chain contains the ligand binding site, the beta chain transverses the membrane and contains the tyrosine protein kinase domain. While only the insulin and the insulin growth factor I receptors are known to exist in the tetrameric conformation specific to class II RTK's, all the above proteins share extensive homologies in their kinase domain, especially around the putative site of autophosphorylation.