Janus kinase

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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 1 General functions of JAKs 2 The Janus kinase family 2.1 JAK1 2.2 JAK2 2.3 JAK3 2.4 TYK2 3 The structure of JAKs 4 Additional images 5 References

[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. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling.^[2]

[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] 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] Further, mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and other myeloproliferative disorders.^[8] This mutation, a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin. Loss of Jak2 is lethal by embryonic day 12 in mice.^[9]

[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.^[10]

[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] Additional images

Key steps of the JAK-STAT pathway

[edit] References