imported>TeaDrinker: add back just another kinase with reference of fact

2025-10-30T14:13:02Z

add back just another kinase with reference of fact

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{{short description|Family of intracellular tyrosine kinases}}
'''Janus kinase''' ('''JAK''') is a family of intracellular, [[Non-receptor tyrosine kinase|non-receptor tyrosine kinases]] that transduce [[cytokine]]-mediated signals via the [[JAK-STAT pathway]]. They were initially named "'''just another kinase'''" 1 and 2 (since they were just two of many discoveries in a [[polymerase chain reaction|PCR]]-based screen of kinases),<ref name = Wilks2>{{cite journal | author=Wilks |title=Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction | journal=PNAS| volume=86 | year=1989 | pages=1603–7 | doi = 10.1073/pnas.86.5.1603| issue=5 | pmid=2466296 | pmc=286746|bibcode=1989PNAS...86.1603W |doi-access=free }}</ref><ref name = Wilks1>{{cite journal | last = Wilks | first = Andrew | title = The JAK kinases: Not just another kinase drug discovery target | journal = Seminars in Cell & Developmental Biology | volume = 19| issue = 4| date= August 2008 | pages = 319-328 | doi =10.1016/j.semcdb.2008.07.020}}</ref> but were ultimately published as "Janus kinase". The name is taken from the two-faced [[Roman mythology|Roman]] god of beginnings, endings and duality, [[Janus (mythology)|Janus]], because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

==Family==
[[Image:Signal transduction pathways.svg|300px|thumb|right|Overview of signal transduction pathways involved in [[apoptosis]]]]
The four JAK family members are:
* [[Janus kinase 1]] (JAK1)
* [[Janus kinase 2]] (JAK2)
* [[Janus kinase 3]] (JAK3)
* [[Tyrosine kinase 2]] (TYK2)

Transgenic mice that do not express JAK1 have defective responses to some cytokines, such as [[interferon-gamma]].<ref name="pmid9590172">{{cite journal |vauthors=Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM, Schreiber RD |title=Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses |journal=Cell |volume=93 |issue=3 |pages=373–83 |year=1998 |pmid=9590172| doi = 10.1016/S0092-8674(00)81166-6|doi-access=free }}</ref> JAK1 and JAK2 are involved in [[type II interferon]] (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved in [[type I interferon]] signalling. Mice that do not express TYK2 have defective [[natural killer cell]] function.<ref name="pmid15578097">{{cite journal |vauthors=Stoiber D, Kovacic B, Schuster C, Schellack C, Karaghiosoff M, Kreibich R, Weisz E, Artwohl M, Kleine OC, Muller M, Baumgartner-Parzer S, Ghysdael J, Freissmuth M, Sexl V |title=TYK2 is a key regulator of the surveillance of B lymphoid tumors |journal=J. Clin. Invest. |volume=114 |issue=11 |pages=1650–8 |year=2004 |pmid=15578097 |doi=10.1172/JCI22315 |pmc=529282}}</ref>

==Functions==
[[Image:Jakstat pathway.svg|thumb|right|The JAK-STAT system consists of three main components:
(1) a receptor (green), which penetrates the cell membrane;
(2) Janus kinase (JAK) (yellow), which is bound to the receptor, and;
(3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates.
After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases.]]

Since members of the [[type I cytokine receptor|type I]] and [[type II cytokine receptor]] families possess no catalytic [[kinase]] activity, they rely on the JAK family of [[tyrosine kinase]]s to [[phosphorylate]] and activate downstream proteins involved in their [[signal transduction]] pathways. The [[Receptor (biochemistry)|receptor]]s exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains.

JAKs associate with a [[proline]]-rich region in each [[intracellular]] domain that is adjacent to the [[cell membrane]] and called a box1/box2 region. After the receptor associates with its respective [[cytokine]]/[[ligand]], it goes through a conformational change, bringing the two JAKs close enough to [[phosphorylate]] each other. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activating [[transcription factor]]s called [[STAT protein|STATs (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription)]].<ref name="Kisselva">{{cite journal | author=Kisseleva |title=Signaling through the JAK/STAT pathway, recent advances and future challenges | journal=Gene | volume=285 | date=2002-02-20 | pages=1–24 | doi=10.1016/S0378-1119(02)00398-0 | issue=1–2 | pmid=12039028 | last2=Bhattacharya | first2=S | last3=Braunstein | first3=J | last4=Schindler | first4=CW |display-authors=etal}}</ref> The activated STATs dissociate from the receptor and form dimers before translocating to the [[cell nucleus]], where they regulate [[Transcription (genetics)|transcription]] of selected [[gene]]s.

Some examples of the molecules that use the JAK/STAT signaling pathway are [[colony-stimulating factor]], [[prolactin]], [[growth hormone]], and many [[cytokines]]. Janus Kinases have also been reported to have a role in the maintenance of [[X chromosome inactivation]].<ref>{{Cite journal |last1=Lee |first1=Hyeong-Min |last2=Kuijer |first2=M. Bram |last3=Ruiz Blanes |first3=Nerea |last4=Clark |first4=Ellen P. |last5=Aita |first5=Megumi |last6=Galiano Arjona |first6=Lorena |last7=Kokot |first7=Agnieszka |last8=Sciaky |first8=Noah |last9=Simon |first9=Jeremy M. |last10=Bhatnagar |first10=Sanchita |last11=Philpot |first11=Benjamin D. |date=2020-11-10 |title=A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance |journal=Journal of Neurodevelopmental Disorders |volume=12 |issue=1 |doi=10.1186/s11689-020-09332-3 |issn=1866-1947|doi-access=free |hdl=11568/1121003 |hdl-access=free |pmc=7657357 }}</ref>

===Clinical significance===
[[JAK inhibitor]]s are used for the treatment of [[atopic dermatitis]] and [[rheumatoid arthritis]]. They are also being studied in [[psoriasis]], [[polycythemia vera]], [[alopecia]], essential [[thrombocythemia]], [[ulcerative colitis]], [[myeloid metaplasia]] with [[myelofibrosis]] and [[vitiligo]].<ref>Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy: D. Golan et al. LWW. 2007</ref><ref name=Craiglow>{{cite journal |author1=Craiglow, B. G. |author2=King, B. A. | title=Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy | journal=JAMA Dermatology | year=2015 | doi = 10.1001/jamadermatol.2015.1520 | pmid = 26107994 | volume=151 |issue=10 | pages=1110–2| doi-access=free }}</ref> Examples are [[tofacitinib]], [[baricitinib]], [[upadacitinib]] and [[filgotinib]].<ref>{{cite web|url=https://clinicaltrials.gov/ct2/results?term=GLPG0634&Search=Search|title=Search of: GLPG0634 - List Results - ClinicalTrials.gov|work=clinicaltrials.gov}}</ref>

In 2014 researchers discovered that oral JAK inhibitors, when administered orally, could restore hair growth in some subjects and that applied to the skin, effectively promoted hair growth.<ref>{{Cite web|title = FDA-approved drugs show promise for rapid and robust hair regrowth|url = http://www.gizmag.com/fda-drug-hair-loss/40037|website = www.gizmag.com|date = 26 October 2015|access-date = 2015-10-29}}</ref>

==Structure==
[[Image:Jak domain structure.svg|thumb|485px|Domain structure of Janus kinases, JH = JAK homology domain]]
JAKs range from 120-140 [[Dalton (unit)|kDa]] in size and have seven defined regions of homology called Janus homology domains 1 to 7 (JH1-7). JH1 is the [[kinase]] domain important for the [[enzyme|enzymatic]] activity of the JAK and contains typical features of a [[tyrosine kinase]] such as conserved [[tyrosine]]s necessary for JAK activation (e.g., Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to the conformational changes in the JAK protein to facilitate binding of [[substrate (biochemistry)|substrate]]. JH2 is a [[pseudokinase domain]], a domain structurally similar to a tyrosine kinase and essential for a normal kinase activity, yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1, and was likely a duplication of the JH1 domain which has undergone mutation post-duplication. The JH3-JH4 domains of JAKs share homology with [[Src (gene)|Src-homology]]-2 ([[SH2 domain|SH2]]) domains. The [[amino terminal]] (NH<sub>2</sub>) end (JH4-JH7) of Jaks is called a [[FERM domain]] (short for [[band 4.1]], [[ezrin]], [[radixin]] and [[moesin]]); this domain is also found in the [[focal adhesion kinase]] (FAK) family and is involved in association of JAKs with [[cytokine]] receptors and/or other kinases.<ref name="Kisselva"/>

==References==
{{Reflist|30em}}

{{JAK-STAT signaling pathway}}
{{Tyrosine kinases}}
{{Enzymes}}
{{Cytokine receptor modulators}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Janus Kinase}}
[[Category:Signal transduction]]
[[Category:Tyrosine kinases]]

Janus kinase - Revision history

imported>TeaDrinker: add back just another kinase with reference of fact