Editing Kinase (section)

==Protein kinases==
[[File:signal transduction pathways.png|thumb|upright=2|right|Overview of signal transduction pathways. Many of the proteins involved are kinases, including protein kinases (such as [[MAPK]] and [[Janus kinase|JAK]]) and lipid kinases (such as [[PI3K]]).]]
{{main|Protein kinase}}
Protein kinases act on proteins, by phosphorylating them on their serine, threonine, tyrosine, or histidine residues. Phosphorylation can modify the function of a protein in many ways. It can increase or decrease a protein's activity, stabilize it or mark it for destruction, localize it within a specific cellular compartment, and it can initiate or disrupt its interaction with other proteins. The protein kinases make up the majority of all kinases and are widely studied.<ref>{{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 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | s2cid = 26554314 | bibcode = 2002Sci...298.1912M }}</ref> These kinases, in conjunction with [[phosphatase]]s, play a major role in protein and [[enzyme]] regulation as well as signalling in the cell.

A common point of confusion arises when thinking about the different ways a cell achieves biological regulation. There are countless examples of covalent modifications that cellular proteins can undergo; however, phosphorylation is one of the few reversible covalent modifications. This provided the rationale that phosphorylation of proteins is regulatory. The potential to regulate protein function is enormous given that there are many ways to covalently modify a protein in addition to regulation provided by allosteric control. In his Hopkins Memorial Lecture, [[Edwin Krebs]] asserted that allosteric control evolved to respond to signals arising from inside the cell, whereas phosphorylation evolved to respond to signals outside of the cell. This idea is consistent with the fact that phosphorylation of proteins occurs much more frequently in [[eukaryote|eukaryotic cells]] in comparison to [[prokaryote|prokaryotic cells]] because the more complex cell type evolved to respond to a wider array of signals.<ref name="krebs lec"/>

===Cyclin dependent kinases===

[[Cyclin dependent kinase]]s (CDKs) are a group of several different kinases involved in regulation of the [[cell cycle]]. They phosphorylate other proteins on their serine or threonine residues, but CDKs must first bind to a [[cyclin]] protein in order to be active.<ref name="cdk review">{{cite journal | vauthors = Harper JW, Adams PD | title = Cyclin-dependent kinases | journal = Chemical Reviews | volume = 101 | issue = 8 | pages = 2511–2526 | date = August 2001 | pmid = 11749386 | doi = 10.1021/cr0001030 }}</ref> Different combinations of specific CDKs and cyclins mark different parts of the cell cycle. Additionally, the phosphorylation state of CDKs is also critical to their activity, as they are subject to regulation by other kinases (such as [[CDK-activating kinase]]) and [[phosphatases]] (such as [[Cdc25]]).<ref>{{cite book| vauthors = Karp G |title=Cell and molecular biology : concepts and experiments|year=2010|publisher=John Wiley|location=Hoboken, NJ|isbn=9780470483374|edition=6th}}</ref> Once the CDKs are active, they phosphorylate other proteins to change their activity, which leads to events necessary for the next stage of the cell cycle. While they are most known for their function in cell cycle control, CDKs also have roles in transcription, metabolism, and other cellular events.<ref>{{cite journal | vauthors = Lim S, Kaldis P | title = Cdks, cyclins and CKIs: roles beyond cell cycle regulation | journal = Development | volume = 140 | issue = 15 | pages = 3079–3093 | date = August 2013 | pmid = 23861057 | doi = 10.1242/dev.091744 | doi-access = free }}</ref>

Because of their key role in the controlling cell division, mutations in CDKs are often found in cancerous cells. These mutations lead to uncontrolled growth of the cells, where they are rapidly going through the whole cell cycle repeatedly.<ref name=can>{{cite journal | vauthors = Canavese M, Santo L, Raje N | title = Cyclin dependent kinases in cancer: potential for therapeutic intervention | journal = Cancer Biology & Therapy | volume = 13 | issue = 7 | pages = 451–457 | date = May 2012 | pmid = 22361734 | doi = 10.4161/cbt.19589 | doi-access = free }}</ref> CDK mutations can be found in [[lymphoma]]s, [[breast cancer]], [[pancreas|pancreatic]] [[tumor]]s, and [[lung cancer]]. Therefore, [[CDK inhibitor|inhibitors of CDK]] have been developed as treatments for some types of cancer.<ref name=can />

===Mitogen-activated protein kinases===
{{main|Mitogen-activated protein kinase}}

[[Mitogen-activated protein kinase|MAP kinases]] (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all considered mitogenic stimuli that can engage the MAPK pathway. Activation of this pathway at the level of the receptor initiates a signaling cascade whereby the [[Ras subfamily|Ras GTPase]] exchanges [[Guanosine diphosphate|GDP]] for [[Guanosine triphosphate|GTP]]. Next, Ras activates [[Raf kinase]] (also known as MAPKKK), which activates [[Mitogen-activated protein kinase kinase|MEK]] (MAPKK). MEK activates [[Mitogen-activated protein kinase|MAPK]] (also known as ERK), which can go on to regulate [[transcription (genetics)|transcription]] and [[translation (biology)|translation]]. Whereas RAF and MAPK are both serine/threonine kinases, MAPKK is a tyrosine/threonine kinase.

[[File:Components of the MAPK Pathway.png|thumb|upright=2|A variety of mitogenic signals engage the MAPK pathway and promote cell growth and differentiation through a kinase cascade.]]

MAPK can regulate transcription factors directly or indirectly. Its major transcriptional targets include ATF-2, Chop, c-Jun, c-Myc, DPC4, Elk-1, Ets1, Max, MEF2C, NFAT4, Sap1a, STATs, Tal, p53, CREB, and Myc. MAPK can also regulate translation by phosphorylating the S6 kinase in the large ribosomal subunit. It can also phosphorylate components in the upstream portion of the MAPK signalling cascade including Ras, Sos, and the [[EGF receptor]] itself.<ref name=MAPK>{{cite journal | vauthors = Garrington TP, Johnson GL | title = Organization and regulation of mitogen-activated protein kinase signaling pathways | journal = Current Opinion in Cell Biology | volume = 11 | issue = 2 | pages = 211–218 | date = April 1999 | pmid = 10209154 | doi = 10.1016/s0955-0674(99)80028-3 }}</ref>

The carcinogenic potential of the MAPK pathway makes it clinically significant. It is implicated in cell processes that can lead to uncontrolled growth and subsequent tumor formation. Mutations within this pathway alter its regulatory effects on [[cell differentiation]], proliferation, survival, and [[apoptosis]], all of which are implicated in various forms of [[cancer]].<ref name=MAPK />