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Tyrosine

Phosphate

ATP

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.

There are over 100 3D structures of tyrosine kinases available at the Protein Data Bank. An example is PDB 1IRK, the crystal structure of the tyrosine kinase domain of the human insulin receptor.

Most tyrosine kinases have an associated protein tyrosine phosphatase.

The tyrosine kinases are divided into two groups:

• those that are cytoplasmic proteins.
• the transmembrane receptor-linked kinases.

Approximately 2000 kinases are known and more than 90 Protein Tyrosine Kinases (PTKs) have been found in the human genome. They are divided into two classes, receptor and non-receptor PTKs. At present, 58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies. They play pivotal roles in diverse cellular activities including growth, differentiation, metabolism, adhesion, motility, death ^[1]. RTKs are composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates. Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation. In particular, movement of some parts of the kinase domain gives free access to adenosine triphosphate (ATP) and the substrate to the active site. This triggers a cascade of events through phosphorylation of intracellular proteins that ultimately transmit ("transduce") the extracellular signal to the nucleus, causing changes in gene expression. Many RTKs are involved in oncogenesis, either by gene mutation, or chromosome translocation ^[2], or simply by over-expression. In every case, the result is a hyper-active kinase, that confers an aberrant, ligand-independent, non-regulated growth stimulus to the cancer cells.

In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 2.7.10.2).

The first non-receptor tyrosine kinase identified was the v-src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases.

A chicken sarcoma virus was found to carry mutated version of the normal cellular Src gene.

The mutated v-src gene has lost the normal built-in inhibition of enzyme activity that is characteristic of cellular SRC (c-src) genes. SRC family members have been found to regulate many cellular processes.

For example, the T-cell antigen receptor leads to intracellular signalling by activation of Lck and Fyn, two proteins that are structurally similar to Src.

Tyrosine kinase is particularly important today because of its implications in the treatment of cancer. A mutation that causes certain tyrosine kinases to be constitutively active has been associated with several cancers. Imatinib (brand names Gleevec and Glivec) is a drug able to bind the catalytic cleft of these tyrosine kinases, inhibiting its activity. ^[3]