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A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). This class of protein is further separated into subsets such as PKC alpha, PKC beta, and PKC gamma, each with specific functions. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. Up to 30% of all proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in 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 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.
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 (imatinib) and Iressa (gefitinib).
Additional recommended knowledge
Serine/threonine-specific protein kinases
Main article: Serine/threonine-specific protein kinases
Serine/threonine protein kinases (EC 18.104.22.168) 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.
Tyrosine-specific protein kinases
Main article: Tyrosine kinase
Tyrosine-specific protein kinases (EC 22.214.171.124) phosphorylate tyrosine amino acid residues, and are, like serine/threonine-specific kinases, used in signal transduction. They act primarily as growth factor receptors and in downstream signaling from growth factors; some examples:
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.
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 α helix. The intracellular or cytoplasmic domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.
Ligand binding causes two reactions:
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".
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 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
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.
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.
|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.|