Protein kinase 24635 219487908 2008-06-15T13:44:02Z 24.3.23.37 [[Image:Inorganic-phosphate-3D-balls.png|right|thumb|Above is a [[ball-and-stick model]] of the [[inorganic]] phosphate [[molecule]] (H<sub></sub>PO<sub>4</sub><sup>2−</sup>). Colour coding: [[phosphorus|P]] (orange); [[oxygen|O]] (red); [[hydrogen|H]] (white).]] 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 (biochemistry)|substrate]]) by changing enzyme [[catalysis|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 [[Adenosine triphosphate|ATP]] and covalently attaching it to one of three [[amino acid]]s 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 protein]]s or [[Enzyme inhibitor|inhibitor protein]]s, 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 == [[Image:CaMKII.png|thumb|100px|Calcium/calmodulin-dependent protein kinase II (CaMKII) is an example of a serine/threonine-specific protein kinase.]] {{main|Serine/threonine-specific protein kinases}} Serine/threonine protein kinases ({{EC number|2.7.11.1}}) 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 [[cyclic adenosine monophosphate|cAMP]]/[[cGMP]], [[diglyceride|Diacylglycerol]], and [[Calcium in biology|Ca<sup>2+</sup>]]/[[calmodulin]]. One very important group of protein kinases are the [[MAP kinase]]s (acronym from: "mitogen/microtubule-activated protein kinases"). Important subgroups are the kinases of the ERK family, which are often activated by mitogenic signals, and stress-activated protein kinases ([[JNK]], p38), which are activated by signals that include intracellular stress. 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<ref>Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc). 2004 Aug;69(8):844-54. Review. PMID: 15377263</ref>. == Tyrosine-specific protein kinases == {{main|Tyrosine kinase}} [[Tyrosine]]-specific protein kinases ({{EC number|2.7.10.1}}) 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 <ref>Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N. Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci. 2008 Feb;99(2):214-20. Review. PMID: 18271917 </ref>; some examples: * [[Platelet-derived growth factor]] (PDGF) receptor; * [[Epidermal growth factor]] (EGF) receptor<ref>Carpenter G. The EGF receptor: a nexus for trafficking and signaling. Bioessays. 2000 Aug;22(8):697-707. Review. PMID: 10918300 </ref>; * [[Insulin]] [[insulin receptor|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 ===<!-- This section is linked from [[Tyrosine kinase]] --> 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 (biochemistry)|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 [[homodimer|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: # [[Dimer]]ization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are [[valence (chemistry)|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. # ''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 protein]]s. (''See [[JAK-STAT pathway]].'') == Histidine-specific protein kinases == [[Histidine]] kinases are structurally distinct from most other protein kinases and are found mostly in [[prokaryote]]s 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 == {{Expand-section|date=June 2008}} ==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 [http://biosupport.licor.com/docs/2005/Olive.pdf 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 [http://www.reactionbiology.com/pages/kinase.htm radioisotope based detections]. ==See also== *[[Protein kinase domain]] - for description of family and list of human protein kinases ==References== {{Reflist|2}} == External links == *[http://pkr.sdsc.edu The Protein Kinase Resource]: Curated database of protein kinase structures and related data *[http://kinase.com Kinase.Com]: Genomics, evolution and large-scale analysis of protein kinases (non-commercial). *[http://www.kinase3d.org/ Kinase3D]: A Database of Protein Kinase 3D homology models provided by [http://www.gen2x.com GEN2X] *[http://www.kinasecentral.com Kinasecentral: Information on Kinase inhibitors in development] *[http://hodgkin.mbu.iisc.ernet.in/~king/ Collection of Ser/Thr/Tyr specific protein kinases and similar sequences] *[http://bioinf.uta.fi/KinMutBase/ KinMutBase: A registry of disease-causing mutations in protein kinase domains] *[http://www.sciencemag.org/cgi/content/abstract/298/5600/1912 Human kinome by Manning et al] *[http://www.reactionbiology.com Profiling for kinase inhibitors]: Radioisotope based gold standard kinase assays * {{UMichOPM|families|superfamily|63}} - Orientations of C1 domains of protein kinases in membranes * {{UMichOPM|families|superfamily|47}} - Orientations of C2 domains of protein kinases and other proteins in membranes ==Further reading== *[http://kinase.com/evolution/TiBS_Kinase_Evolution.pdf Evolution of protein kinase signaling from yeast to man] (pdf) *[http://www.sigtrans.org/publications/pkiRev A review on inhibitors of signal transduction protein kinases as targets for cancer therapy] {{Cell_signaling}} {{Kinases}} [[Category:EC 2.7]] [[Category:Protein kinases]] [[de:Proteinkinase]] [[es:Proteína quinasa]] [[fr:Protéine kinase]] [[he:פרוטאין קינאז]] [[ja:プロテインキナーゼ]] [[pl:Kinazy białkowe]] [[fi:Proteiinikinaasi]] [[sv:Proteinkinas]] [[zh:蛋白激酶]]