Protein kinase

A protein kinase is a

.

Chemical activity

inorganic phosphate molecule (HPO₄²⁻). Colour coding: P (orange); O (red); H

(white).

The chemical activity of a protein kinase involves removing a phosphate group from

Structure

Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core.^[5][6][7][8] The structures of over 280 human protein kinases have been determined.^[9]

There are a number of conserved regions in the catalytic domain of protein kinases. In the

Serine/threonine-specific protein kinases

Serine/threonine protein kinases (EC 2.7.11.1) phosphorylate the OH group of serine or threonine (which have similar side chains). Activity of these protein kinases can be regulated by specific events (e.g., DNA damage), as well as numerous chemical signals, including cAMP/cGMP, diacylglycerol, and Ca²⁺/calmodulin. One very important group of protein kinases are the

and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation.

Tyrosine-specific protein kinases

Tyrosine-specific protein kinases (EC 2.7.10.1 and EC 2.7.10.2) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors.^[11] Some examples include:

• Platelet-derived growth factor receptor (PDGFR)
• Epidermal growth factor receptor (EGFR)^[12]
• Insulin receptor and insulin-like growth factor 1 receptor (IGF1R)
• Stem cell factor (SCF) receptor (also called c-kit, see the article on gastrointestinal stromal tumor
  ).

Receptor tyrosine kinases

These kinases consist of extracellular domains, a transmembrane spanning alpha helix, and an intracellular tyrosine kinase domain protruding into the cytoplasm. They play important roles in regulating cell division, cellular differentiation, and morphogenesis. More than 50 receptor tyrosine kinases are known in mammals.

Structure

The extracellular domains serve as the

is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.

Regulation

Ligand binding causes two reactions:

1. Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are multivalent. Some tyrosine receptor kinases (e.g., the platelet-derived growth factor receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal.
2. Trans-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase.

Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby".

Signal transduction

The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the

signal-transduction chain.

Receptor-associated tyrosine kinases

Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a number of signaling cascades, in particular those involved in

.)

Dual-specificity protein kinases

Some kinases have

cascade, is a both a serine/threonine and tyrosine kinase.

Histidine-specific protein kinases

residue on a 'receiver domain' on a different protein, or sometimes on the kinase itself. The aspartyl phosphate residue is then active in signaling.

Histidine kinases are found widely in prokaryotes, as well as in plants, fungi and eukaryotes. The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate.

Aspartic acid/glutamic acid-specific protein kinases

This section needs expansion. You can help by adding to it. (June 2008)

Inhibitors

Deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (imatinib) and Iressa (gefitinib).

• Anthra(1,9-cd)pyrazol-6(2H)-one
• Staurosporine

Kinase assays and profiling

Drug developments for kinase inhibitors are started from kinase assays, the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays to radioisotope based detections, and competition binding assays.

References

External links

• Human and mouse protein kinases in UniProt: classification and index
• Kinase.Com: Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
• KinMutBase: A registry of disease-causing mutations in protein kinase domains
• KLIFS (Kinase-Ligand Interaction Fingerprints and Structures) Database -- analysis of kinase structures and kinase-inhibitor interactions
• KinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny
• Kinomer: A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases.