Janus kinase
From Wikipedia, the free encyclopedia
Janus kinase (JAK) is a family of intracellular non-receptor tyrosine kinases, ranging from 120-140 kDa, that transduce cytokine-mediated signals via the JAK-STAT pathway. Janus kinase was initially named JAK after "just another kinase." Later, it was said to be named after Janus, the Thessalian gatekeeper of heaven worshipped by Romans. He is described as having two faces. The kinase is named after him because it has two phosphate-transferring domains (only one of which has a known biological role).
Contents |
[edit] General functions of JAKs
Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. JAKs associate with a proline-rich region in the intracellular domain of these receptors, which 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 JAKs close enough to phosphorylate each other. Once phosphorylated/activated, the JAKs transduce an intracellular signal by promoting and activating transcription factors called STATs.[1] The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus where they regulate transcription of selected genes.
[edit] The Janus kinase family
Janus kinase 1
|
|
Identifiers | |
Symbol(s) | JAK1 JAK1B |
Entrez | 3716 |
OMIM | 147795 |
Janus kinase 2
|
|
Identifiers | |
Symbol(s) | JAK2 |
Entrez | 3717 |
OMIM | 147796 |
Janus kinase 3
|
|
Identifiers | |
Symbol(s) | JAK3 |
Entrez | 3718 |
OMIM | 600173 |
tyrosine kinase 2
|
|
Identifiers | |
Symbol(s) | TYK2 |
Entrez | 7297 |
OMIM | 176941 |
There are four JAK family members, JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2). Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon-gamma[2]. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell function[3].
[edit] JAK1
JAK1 is essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, IL-7R, IL-9R and IL-15R), the IL-4 receptor family (e.g. IL-4R and IL-13R), the gp130 receptor family (e.g. IL-6R, IL-11R, LIF-R, OSM-R, cardiotrophin-1 receptor (CT-1R), ciliary neurotrophic factor receptor (CNTF-R), neurotrophin-1 receptor (NNT-1R) and Leptin-R). It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors.[4][1]. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families.
[edit] JAK2
Jak2 has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family (IL-3R, IL-5R and GM-CSF-R), the gp130 receptor family (e.g IL-6R), and the single chain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R).[1] Mutation in JAK2 (creating an amino acid change, V617F) has been associated with myeloproliferative disorders, most specifically with polycythemia vera. JAK2 signaling is activated downstream from the prolactin receptor[5]. JAK2 gene fusions with the TEL(ETV6) (TEL-JAK2) and PCM1 genes have been found in leukemia patients.[6][7]
[edit] JAK3
Since Jak3 expression is restricted mostly to hematopoietic cells, its role in cytokine signaling is thought to be more restricted than other JAKs. Jak3 is involved in signal transduction by receptors that employ the common gamma chain (γC) of the type I cytokine receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R).).[1] Mutations of JAK3 result in severe combined immunodeficiency (SCID). Mice that do not express JAK3 have T-cells and B-cells that fail to respond to many cytokines [8].
[edit] TYK2
Tyk2, was the first member of the JAK family that was described. It has been implicated in IFN-α, IL-6, IL-10 and IL-12 signaling.[1]
[edit] The structure of JAKs
JAKs have seven defined regions of homology; these are called Janus homology domain 1–7 (JH1-7). JH1 is the kinase domain important for the enzymatic activity of the JAK and contains typical features of a tyrosine kinase such as conserved tyrosines 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. JH2 is a pseudokinase domain, a domain structurally similar to a tyrosine kinase and is essential for a normal kinase activity yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1. The JH3-JH4 domain of JAKs shares homology with Src-homology-2 (SH2) domains. The amino terminal (NH2) 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.[4][1]
[edit] References
- ^ a b c d e f Kisseleva et al., Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene Volume 285, Issues 1-2 , 20 February 2002, Pages 1-24.
- ^ S. Rodig, M. Meraz, J. White, P. Lampe, J. Riley, C. Arthur, K. King, K. Sheehan, L. Yin, D. Pennica, E. Johnson and R. Schreiber (1998) "Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses" in Cell Volume 93, pages 373-383. Entrez PubMed 9590172
- ^ D. Stoiber, B. Kovacic, C. Schuster, C. Schellack, M. Karaghiosoff , R. Kreibich, E. Weisz, M. Artwohl, O. Kleine, M. Muller, S. Baumgartner-Parzer, J. Ghysdael, M. Freissmuth and V. Sexl (2004) "TYK2 is a key regulator of the surveillance of B lymphoid tumors" in Journal of Clinical Investigaion Volume 114, pages 1650-1658. Entrez PubMed 15578097
- ^ a b Gadina et al. Signaling by Type I and II cytokine receptors: ten years after. Current Opinion in Immunology, Volume 13, Issue 3 , 1 June 2001, Pages 363-373.
- ^ Christine Bole-Feysot1, Vincent Goffin1, Marc Edery, Nadine Binart and Paul A. Kelly (1998) "Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice" in Endocrine Reviews Volume 19, pages 225-268. Entrez PubMed 9626554
- ^ Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA (1997) "A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia" in Science Volume 278 (5341), pages 1309-12. Entrez PubMed 9360930
- ^ Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, Cross NC (2005) "The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2" in Cancer Res Volume 65 (7), pages 2662-67. Entrez PubMed 15805263
- ^ T. Nosaka, J. van Deursen, R. Tripp, W. Thierfelder, B. Witthuhn, A. McMickle, P. Doherty, G. Grosveld and J. Ihle (1995) "Defective lymphoid development in mice lacking Jak3" in Science Volume 270, pages 800-802. Entrez PubMed 7481769
Cell signaling |
---|
Key concepts - Ligand | Receptor | Second messenger | Protein kinase | Transcription factor | Cell signaling networks |
Pathways - Apoptosis | Ca2+ signaling | Cytokine signaling | Hedgehog | Integrin signaling | JAK/STAT | Lipid signaling | MAPK/ERK pathway | mTOR | NF-kB | Notch | p53 | TGFβ | Wnt |