Janus kinase (JAK) is a family of intracellular,non-receptor tyrosine kinases that 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-facedRoman god 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.
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 interferon signalling. Mice that do not express TYK2 have defectivenatural killer cell function.[3]
Since members of thetype I andtype II cytokine receptor families possess no catalytickinase activity, they rely on the JAK family oftyrosine kinases tophosphorylate and activate downstream proteins involved in theirsignal transduction pathways. Thereceptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains.
JAKs associate with aproline-rich region in eachintracellular domain that is adjacent to thecell membrane and 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 tophosphorylate each other. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activatingtranscription factors calledSTATs (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 regulatetranscription of 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]
JAK inhibitors are used for the treatment ofatopic dermatitis andrheumatoid arthritis. They are also being studied inpsoriasis,polycythemia vera,alopecia, essentialthrombocythemia,ulcerative colitis,myeloid metaplasia withmyelofibrosis andvitiligo.[6][7] Examples aretofacitinib,baricitinib,upadacitinib andfilgotinib.[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]
JAKs range from 120-140kDa in size and have seven defined regions of homology called Janus homology domains 1 to 7 (JH1-7). JH1 is thekinase domain important for theenzymatic activity of the JAK and contains typical features of atyrosine kinase such as conservedtyrosines 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 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,radixin andmoesin); this domain is also found in thefocal adhesion kinase (FAK) family and is involved in association of JAKs withcytokine receptors and/or other kinases.[4]
