Editing Protein kinase

{{Short description|Enzyme that adds phosphate groups to other proteins}}
[[File:Kinase function.png|thumb|upright=1.5|right|General scheme of [[kinase]] function]]
A '''protein kinase''' is a [[kinase]] which selectively modifies other proteins by covalently adding [[phosphate]]s to them ([[Protein phosphorylation|phosphorylation]]) as opposed to kinases which modify lipids, carbohydrates, or other molecules. 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. The [[human genome]] contains about 500 protein kinase genes and they constitute about 2% of all human genes.<ref name="pmid12471243"/> There are two main types of protein kinase. The great majority are [[Serine/threonine-specific protein kinase|serine/threonine kinases]], which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are [[tyrosine kinase]]s, although additional types exist.<ref name="Alberts"/> Protein kinases are also found in [[bacteria]] and [[plants]]. 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 in [[signal transduction]].

==Chemical activity==
[[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).]]
The chemical activity of a protein 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 kinase]]s) act on all three.<ref name="pmid9779990"/> There are also protein kinases that phosphorylate other amino acids, including [[histidine kinase]]s that phosphorylate histidine residues.<ref name="pmid12531242"/>

==Structure==
{{main|Protein kinase domain}}
Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core.<ref name="pmid12734000"/><ref name="pmid7768349"/><ref name="pmid1835513"/><ref name="pmid1956325"/>  The structures of over 280 human protein kinases have been determined.<ref name="pmid31875044"/>

There are a number of conserved regions in the catalytic domain of protein kinases. In the [[N-terminal]] extremity of the catalytic domain there is a [[glycine]]-rich stretch of residues in the vicinity of a [[lysine]] amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conserved [[aspartic acid]], which is important for the catalytic activity of the enzyme.<ref name="pmid1862342"/>

== Serine/threonine-specific protein kinases ==
[[Image:CaMKII.png|thumb|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 side chains). 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]]/[[Cyclic guanosine monophosphate|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-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.<ref>{{Cite journal |last1=Hanks |first1=Steven K. |last2=Hunter |first2=Tony |date=1995 |title=The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification |journal=The FASEB Journal |language=en |volume=9 |issue=8 |pages=576–596 |doi=10.1096/fasebj.9.8.7768349 |doi-access=free |issn=1530-6860}}</ref>

== Tyrosine-specific protein kinases ==
{{main|Tyrosine kinase}}
[[Tyrosine]]-specific protein kinases ({{EC number|2.7.10.1}} and {{EC number|2.7.10.2}}) 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.<ref name="pmid18271917"/> Some examples include:
* [[Platelet-derived growth factor receptor]] (PDGFR)
* [[Epidermal growth factor receptor]] (EGFR)<ref name="pmid10918300"/>
* [[Insulin receptor]] and [[insulin-like growth factor 1 receptor]] (IGF1R)
* [[C-KIT|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]] -->
{{Main|Receptor tyrosine kinase}}
These kinases consist of extracellular domains, a transmembrane spanning [[alpha helix]], and an intracellular [[tyrosine kinase]] domain protruding into the [[cytoplasm]]. They play important roles in regulating [[cell division]], [[cellular differentiation]], and [[morphogenesis]]. More than 50 receptor tyrosine kinases are known in mammals.<ref>{{Cite journal |last1=Robinson |first1=Dan R. |last2=Wu |first2=Yi-Mi |last3=Lin |first3=Su-Fang |date=November 2000 |title=The protein tyrosine kinase family of the human genome |url=https://www.nature.com/articles/1203957 |journal=Oncogene |language=en |volume=19 |issue=49 |pages=5548–5557 |doi=10.1038/sj.onc.1203957 |pmid=11114734 |issn=1476-5594}}</ref>

==== Structure ====
The extracellular domains serve as the [[ligand (biochemistry)|ligand]]-binding part of the molecule, often inducing the domains to form [[homodimer|homo-]] or [[heterodimer]]s. The transmembrane element is a single α helix. The intracellular or cytoplasmic [[Protein kinase domain]] is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.{{cn|date=June 2024}}

==== Regulation ====
Ligand binding causes two reactions:
# [[Protein dimer|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.

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".

==== 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.{{cn|date=June 2024}}

===Receptor-associated tyrosine kinases===
{{main|Non-receptor tyrosine kinase}}
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 in [[cytokine]] signaling (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]].'')

==Dual-specificity protein kinases==
{{main|Dual-specificity kinase}}
Some kinases have [[dual-specificity kinase]] activities. For example, [[Mitogen-activated protein kinase kinase|MEK]] (MAPKK), which is involved in the [[MAP kinase]] cascade, is a both a serine/threonine and tyrosine kinase.

==Histidine-specific protein kinases==
[[Histidine kinase]]s 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, 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==
{{Expand-section|date=June 2008}}

==Inhibitors==
{{main|Protein kinase inhibitor}}
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]]).
* [[Anthra(1,9-cd)pyrazol-6(2H)-one]]
* [[Staurosporine]]

==Kinase assays and profiling==
Drug developments for kinase inhibitors are started from [http://biosupport.licor.com/docs/2005/Olive.pdf kinase assays] {{Webarchive|url=https://web.archive.org/web/20141126233119/http://biosupport.licor.com/docs/2005/Olive.pdf |date=2014-11-26 }}, the lead compounds are usually profiled for specificity before moving into further tests.  Many profiling services are available from fluorescent-based assays to [https://web.archive.org/web/20070517125440/http://www.reactionbiology.com/pages/kinase.htm radioisotope based detections], and [http://www.kinomescan.com competition binding assays].

==References==
{{Reflist|refs=

<ref name="pmid12471243">{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S| title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–1934 | year = 2002 | pmid = 12471243 | doi = 10.1126/science.1075762| bibcode = 2002Sci...298.1912M | s2cid = 26554314 }}</ref>

<ref name="Alberts">{{Cite book |last=Alberts, Bruce |title=Molecular biology of the cell |date=18 November 2014 |isbn=978-0-8153-4432-2 |edition=Sixth |location=New York |pages=819–820 |oclc=887605755}}</ref>

<ref name="pmid9779990">{{cite journal |vauthors=Dhanasekaran N, Premkumar Reddy E |title=Signaling by dual specificity kinases |journal=Oncogene |volume=17 |issue=11 Reviews |pages=1447–55 |date=September 1998 |pmid=9779990 |doi=10.1038/sj.onc.1202251 |s2cid=9299657 |doi-access= }}</ref>

<ref name="pmid12531242">{{cite journal |vauthors=Besant PG, Tan E, Attwood PV |title=Mammalian protein histidine kinases |journal=[[Int. J. Biochem. Cell Biol.]] |volume=35 |issue=3 |pages=297–309 |date=March 2003 |pmid=12531242 |doi= 10.1016/S1357-2725(02)00257-1}}</ref>

<ref name="pmid31875044">{{cite journal |last1=Modi |first1=V |last2=Dunbrack |first2=RL |title=A Structurally-Validated Multiple Sequence Alignment of 497 Human Protein Kinase Domains. |journal=Scientific Reports |date=2019-12-24 |volume=9 |issue=1 |pages=19790 |doi=10.1038/s41598-019-56499-4 |pmid=31875044|pmc=6930252 |bibcode=2019NatSR...919790M }}</ref>

<ref name="pmid12734000">{{cite journal | vauthors = Hanks SK | title = Genomic analysis of the eukaryotic protein kinase superfamily: a perspective | journal = Genome Biol. | volume = 4 | issue = 5 | pages = 111 | year = 2003 | pmid = 12734000 | pmc = 156577 | doi = 10.1186/gb-2003-4-5-111 | doi-access = free }}</ref>

<ref name="pmid7768349">{{cite journal | vauthors = Hanks SK, Hunter T | title = Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification | journal = FASEB J. | volume = 9 | issue = 8 | pages = 576–96 | date = May 1995 | pmid = 7768349 | doi = 10.1096/fasebj.9.8.7768349| doi-access = free | s2cid = 21377422 | url = http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=7768349 }}</ref>

<ref name="pmid1835513">{{cite book | vauthors = Hunter T | title = Protein Phosphorylation Part A: Protein Kinases: Assays, Purification, Antibodies, Functional Analysis, Cloning, and Expression | chapter = Protein kinase classification | series = Methods in Enzymology | volume = 200 | pages = 3–37 | year = 1991 | pmid = 1835513 | doi = 10.1016/0076-6879(91)00125-G| isbn = 9780121821012 }}</ref>

<ref name="pmid1956325">{{cite book | vauthors = Hanks SK, Quinn AM | title = Protein Phosphorylation Part A: Protein Kinases: Assays, Purification, Antibodies, Functional Analysis, Cloning, and Expression | chapter = Protein kinase catalytic domain sequence database: Identification of conserved features of primary structure and classification of family members | series = Methods in Enzymology | volume = 200 | pages = 38–62 | year = 1991 | pmid = 1956325 | doi = 10.1016/0076-6879(91)00126-H| isbn = 9780121821012 }}</ref> 

<ref name="pmid1862342">{{cite journal | vauthors = Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM | title = Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase | journal = Science | volume = 253 | issue = 5018 | pages = 407–14 | date = July 1991 | pmid = 1862342 | doi = 10.1126/science.1862342 | bibcode = 1991Sci...253..407K }}</ref>

<ref name="pmid18271917">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>

<ref name="pmid10918300">Carpenter G. The EGF receptor: a nexus for trafficking and signaling.
Bioessays. 2000 Aug;22(8):697-707. Review. PMID: 10918300 </ref>
}}

== External links ==
{{Portal|Biology}}
* [https://www.uniprot.org/docs/pkinfam Human and mouse protein kinases in UniProt: classification and index]
* [http://kinase.com/web/current/ Kinase.Com]: Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
* [http://structure.bmc.lu.se/idbase/KinMutBase/ KinMutBase: A registry of disease-causing mutations in protein kinase domains] {{Webarchive|url=https://web.archive.org/web/20220615180841/http://structure.bmc.lu.se/idbase/KinMutBase/ |date=2022-06-15 }}
* [https://klifs.net KLIFS (Kinase-Ligand Interaction Fingerprints and Structures) Database -- analysis of kinase structures and kinase-inhibitor interactions]
* [http://dunbrack.fccc.edu/kincore KinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny]
* [http://www.compbio.dundee.ac.uk/kinomer/index.html Kinomer: A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases.]
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{{DEFAULTSORT:Protein Kinase}}
[[Category:EC 2.7]]
[[Category:Protein kinases]]