Protein kinase



  A protein kinase is a signal transduction, the transmission of signals within the cell. The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes.

The chemical activity of a kinase involves removing a phosphate group from tyrosine, and a number (dual specificity kinases) act on all three.

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.

Disregulated 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 (gefitinib).

Serine/threonine-specific protein kinases

 

Main article: Serine/threonine-specific protein kinases

Serine/threonine protein kinases (calmodulin.

Tyrosine-specific protein kinases

Main article: Tyrosine kinase

growth factor receptors and in downstream signaling from growth factors; some examples:

Receptor tyrosine kinases

These kinases consist of 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 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 α 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 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 JAK-STAT pathway.)

Histidine-specific protein kinases

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 and fungi. 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

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

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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TFIID, TFIIH) - Adaptor protein
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Phosphotransferases/Tyrosine - Serine/threonine-specific
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Protein_kinase". A list of authors is available in Wikipedia.