Aprotein kinase is akinase which selectively modifies other proteins by covalently addingphosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzymeactivity, cellular location, or association with other proteins. Thehuman genome contains about 500 protein kinase genes and they constitute about 2% of all human genes.[1] There are two main types of protein kinase. The great majority areserine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others aretyrosine kinases, although additional types exist.[2] Protein kinases are also found inbacteria andplants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved insignal transduction.
The chemical activity of a protein kinase involves removing a phosphate group fromATP and covalently attaching it to one of threeamino acids that have a freehydroxyl group. Most kinases act on bothserine andthreonine, others act ontyrosine, and a number (dual-specificity kinases) act on all three.[3] There are also protein kinases that phosphorylate other amino acids, includinghistidine kinases that phosphorylate histidine residues.[4]
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 theN-terminal extremity of the catalytic domain there is aglycine-rich stretch of residues in the vicinity of alysine amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conservedaspartic acid, which is important for the catalytic activity of the enzyme.[10]
Serine/threonine protein kinases (EC2.7.11.1) phosphorylate the OH group ofserine orthreonine (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, includingcAMP/cGMP,diacylglycerol, andCa2+/calmodulin.One very important group of protein kinases are theMAP kinases (acronym from: "mitogen-activated protein kinases"). Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinasesJNK 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.[11]
Tyrosine-specific protein kinases (EC2.7.10.1 andEC2.7.10.2) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used insignal transduction. They act primarily asgrowth factor receptors and in downstream signaling from growth factors.[12] Some examples include:
These kinases consist of extracellular domains, a transmembrane spanningalpha helix, and an intracellulartyrosine kinase domain protruding into thecytoplasm. They play important roles in regulatingcell division,cellular differentiation, andmorphogenesis. More than 50 receptor tyrosine kinases are known in mammals.[14]
The extracellular domains serve as theligand-binding part of the molecule, often inducing the domains to formhomo- orheterodimers. The transmembrane element is a single α helix. The intracellular or cytoplasmicProtein kinase domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.[citation needed]
Ligand binding causes two reactions:
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".
The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is theras protein signal-transduction chain.[citation needed]
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 incytokine signaling (but also others, includinggrowth hormone). One such receptor-associated tyrosine kinase isJanus kinase (JAK), many of whose effects are mediated bySTAT proteins. (SeeJAK-STAT pathway.)
Some kinases havedual-specificity kinase activities. For example,MEK (MAPKK), which is involved in theMAP kinase cascade, is a both a serine/threonine and tyrosine kinase.
Histidine kinases are structurally distinct from most other protein kinases and are found mostly inprokaryotes 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 anaspartate 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. Thepyruvate 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.
![[icon]](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aWiki_letter_w_cropped.svg) | This sectionneeds expansion. You can help byadding to it.(June 2008) |
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).
Drug developments for kinase inhibitors are started fromkinase assaysArchived 2014-11-26 at theWayback Machine, the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays toradioisotope based detections, andcompetition binding assays.
{{cite book}}: CS1 maint: location missing publisher (link)
