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Janus kinase

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Janus kinase(JAK) is a family of intracellular,non-receptor tyrosine kinasesthat transducecytokine-mediated signals via theJAK-STAT pathway.They were initially named "just another kinase"1 and 2 (since they were just two of many discoveries in aPCR-based screen of kinases),[1]but were ultimately published as "Janus kinase". The name is taken from the two-facedRomangod of beginnings, endings and duality,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[edit]

Overview of signal transduction pathways involved inapoptosis

The four JAK family members are:

Transgenic mice that do not express JAK1 have defective responses to some cytokines, such asinterferon-gamma.[2]JAK1 and JAK2 are involved intype II interferon(interferon-gamma) signalling, whereas JAK1 and TYK2 are involved intype I interferonsignalling. Mice that do not express TYK2 have defectivenatural killer cellfunction.[3]

Functions[edit]

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 thetype Iandtype II cytokine receptorfamilies possess no catalytickinaseactivity, they rely on the JAK family oftyrosine kinasestophosphorylateand activate downstream proteins involved in theirsignal transductionpathways. Thereceptorsexist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains.

JAKs associate with aproline-rich region in eachintracellulardomain that is adjacent to thecell membraneand called a box1/box2 region. After the receptor associates with its respectivecytokine/ligand,it goes through a conformational change, bringing the two JAKs close enough tophosphorylateeach other. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activatingtranscription factorscalledSTATs (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription).[4]The activated STATs dissociate from the receptor and form dimers before translocating to thecell nucleus,where they regulatetranscriptionof selectedgenes.

Some examples of the molecules that use the JAK/STAT signaling pathway arecolony-stimulating factor,prolactin,growth hormone,and manycytokines.Janus Kinases have also been reported to have a role in the maintenance ofX chromosome inactivation.[5]

Clinical significance[edit]

JAK inhibitorsare used for the treatment ofatopic dermatitisandrheumatoid arthritis.They are also being studied inpsoriasis,polycythemia vera,alopecia,essentialthrombocythemia,ulcerative colitis,myeloid metaplasiawithmyelofibrosisandvitiligo.[6][7]Examples aretofacitinib,baricitinib,upadacitinibandfilgotinib.[8]

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.[9]

Structure[edit]

Domain structure of Janus kinases, JH = JAK homology domain

JAKs range from 120-140kDain size and have seven defined regions of homology called Janus homology domains 1 to 7 (JH1-7). JH1 is thekinasedomain important for theenzymaticactivity of the JAK and contains typical features of atyrosine kinasesuch as conservedtyrosinesnecessary 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 ofsubstrate.JH2 is apseudokinase 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 withSrc-homology-2 (SH2) domains. Theamino terminal(NH2) end (JH4-JH7) of Jaks is called aFERM domain(short forband 4.1,ezrin,radixinandmoesin); this domain is also found in thefocal adhesion kinase(FAK) family and is involved in association of JAKs withcytokinereceptors and/or other kinases.[4]

References[edit]

  1. ^Wilks (1989)."Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction".PNAS.86(5): 1603–7.Bibcode:1989PNAS...86.1603W.doi:10.1073/pnas.86.5.1603.PMC286746.PMID2466296.
  2. ^Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM, Schreiber RD (1998)."Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses".Cell.93(3): 373–83.doi:10.1016/S0092-8674(00)81166-6.PMID9590172.
  3. ^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 (2004)."TYK2 is a key regulator of the surveillance of B lymphoid tumors".J. Clin. Invest.114(11): 1650–8.doi:10.1172/JCI22315.PMC529282.PMID15578097.
  4. ^abKisseleva; Bhattacharya, S; Braunstein, J; Schindler, CW; et al. (2002-02-20). "Signaling through the JAK/STAT pathway, recent advances and future challenges".Gene.285(1–2): 1–24.doi:10.1016/S0378-1119(02)00398-0.PMID12039028.
  5. ^Lee, Hyeong-Min; Kuijer, M. Bram; Ruiz Blanes, Nerea; Clark, Ellen P.; Aita, Megumi; Galiano Arjona, Lorena; Kokot, Agnieszka; Sciaky, Noah; Simon, Jeremy M.; Bhatnagar, Sanchita; Philpot, Benjamin D. (2020-11-10)."A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance".Journal of Neurodevelopmental Disorders.12(1).doi:10.1186/s11689-020-09332-3.hdl:11568/1121003.ISSN1866-1947.
  6. ^Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy: D. Golan et al. LWW. 2007
  7. ^Craiglow, B. G.; King, B. A. (2015)."Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy".JAMA Dermatology.151(10): 1110–2.doi:10.1001/jamadermatol.2015.1520.PMID26107994.
  8. ^"Search of: GLPG0634 - List Results - ClinicalTrials.gov".clinicaltrials.gov.
  9. ^"FDA-approved drugs show promise for rapid and robust hair regrowth".www.gizmag.com.26 October 2015.Retrieved2015-10-29.
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