Above is a ball-and-stick model of the inorganic phosphate molecule (H_{PO4^2?). Colour coding: P (orange); O (red); H (white).}

The chemical activity of a kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group. Most kinases act on both serine and threonine, others act on tyrosine, and a number (dual specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.

Because protein kinases have profound effects on a cell, their activity is highly regulated. Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation/autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.

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

Serine/threonine-specific protein kinases

Calcium/calmodulin-dependent protein kinase II (CaMKII) is an example of a serine/threonine-specific protein kinase.

Serine/threonine protein kinases () phosphorylate the OH group of serine or threonine (which have similar sidechains). 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 MAP kinases (acronym from: "mitogen/microtubule-activated protein kinases"). Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases JNK 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. Two major factors influence activity of MAP kinases: a) signals that activate transmembrane receptors (either natural ligands, or crosslinking agents) and proteins associated with them (mutations that simulate active state), b) signals that inactivate the phosphatases that restrict a given MAP kinase. Such signals include oxidant stress^[1].

Tyrosine-specific protein kinases

Tyrosine-specific protein kinases ( and ) 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 ^[2]; some examples:

• Platelet-derived growth factor (PDGF) receptor;
• Epidermal growth factor (EGF) receptor^[3]

Bioessays. 2000 Aug;22(8):697-707. Review. PMID: 10918300 ;

• Insulin receptor and insulin-like growth factor (IGF1) receptor;
• Stem cell factor (SCF) receptor (also called c-kit, see the article on gastrointestinal stromal tumor).

Receptor tyrosine kinases

These kinases consist of a transmembrane receptor with a tyrosine kinase domain protruding into the cytoplasm. They play an important role in regulating cell division, cellular differentiation, and morphogenesis. More than 50 receptor tyrosine kinases are known in mammals.

Structure

The extracellular domain serves as the ligand-binding part of the molecule. It can be a separate unit that is attached to the rest of the receptor by a disulfide bond. The same mechanism can be used to bind two receptors together to form a homo- or heterodimer. The transmembrane element is a single ? helix. The intracellular or cytoplasmic domain 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.

The autophosphorylation causes the two subdomains of the intrinsic kinase to shift, opening the kinase domain for ATP binding. In the inactive form, the kinase subdomains are aligned so that ATP cannot reach the catalytic center of the kinase. 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 is said to be a cis-autophosphorylation, switching 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 ras protein 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 signalling cascades, principally those involved in cytokine signalling (but also others, including growth hormone). One such receptor-associated tyrosine kinase is Janus kinase (JAK), many of whose effects are mediated by STAT proteins. (See JAK-STAT pathway.)

Histidine-specific protein kinases

Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an aspartate 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

Mixed kinases

Some kinases have mixed kinase activities. For example, MEK (MAPKK), which is involved in the MAP kinase cascade, is a mixed serine/threonine and tyrosine kinase.

Inhibitors

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

See also Protein kinase inhibitor

Kinase assays and profilings

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.

See also

• Protein kinase domain - for description of family and list of human protein kinases

References

External links

• The Protein Kinase Resource: (new link!)Curated database of protein kinase structures and related data
• Kinase.Com: Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
• Kinase3D: A Database of Protein Kinase 3D homology models provided by GEN2X
• Kinasecentral: Information on Kinase inhibitors in development
• Collection of Ser/Thr/Tyr specific protein kinases and similar sequences
• KinMutBase: A registry of disease-causing mutations in protein kinase domains
• Human kinome by Manning et al
• Profiling for kinase inhibitors: Radioisotope based gold standard kinase assays
• - Orientations of C1 domains of protein kinases in membranes
• - Orientations of C2 domains of protein kinases and other proteins in membranes

Further reading

• Evolution of protein kinase signaling from yeast to man (pdf)
• A review on inhibitors of signal transduction protein kinases as targets for cancer therapy

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