Janus kinase 2

Janus kinase 2
PDB rendering based on 2b7a.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2B7A​, 2W1I​, 2XA4​, 3E62​, 3E63​, 3E64​, 3FUP​, 3IO7​, 3IOK​, 3JY9​, 3KCK​, 3KRR​, 3LPB​, 3Q32​, 3RVG​, 3TJC​, 3TJD​, 3UGC​, 3ZMM​, 4AQC​, 4BBE​, 4BBF​, 4C61​, 4C62​, 4D0W​, 4D0X​, 4D1S​, 4E4M​, 4E6D​, 4E6Q​, 4F08​, 4F09​, 4FVP​, 4FVQ​, 4FVR​, 4GFM​, 4GMY​, 4HGE​, 4IVA​, 4JI9​, 4JIA​, 4P7E​, 4ZIM​, 5AEP​
Identifiers
Symbols	JAK2 ; JTK10; THCYT3
External IDs	OMIM: 147796 HomoloGene: 21033 ChEMBL: 2971 GeneCards: JAK2 Gene
EC number	2.7.10.2
Gene ontology Molecular function • protein kinase activity • protein tyrosine kinase activity • non-membrane spanning protein tyrosine kinase activity • receptor binding • growth hormone receptor binding • interleukin-12 receptor binding • protein binding • ATP binding • protein C-terminus binding • protein kinase binding • heme binding • type 1 angiotensin receptor binding • acetylcholine receptor binding • histone kinase activity (H3-Y41 specific) • SH2 domain binding • histone binding • phosphatidylinositol 3-kinase binding • insulin receptor substrate binding • peptide hormone receptor binding Cellular component • nucleus • nucleoplasm • cytoplasm • cytosol • cytoskeleton • caveola • nuclear matrix • extrinsic component of cytoplasmic side of plasma membrane • endosome lumen • membrane raft Biological process • activation of MAPKK activity • adaptive immune response • chromatin organization • protein phosphorylation • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • movement of cell or subcellular component • signal transduction • enzyme linked receptor protein signaling pathway • G-protein coupled receptor signaling pathway • positive regulation of cytosolic calcium ion concentration • JAK-STAT cascade • tyrosine phosphorylation of STAT protein • STAT protein import into nucleus • mesoderm development • blood coagulation • positive regulation of cell proliferation • negative regulation of cell proliferation • intrinsic apoptotic signaling pathway in response to oxidative stress • hormone-mediated signaling pathway • negative regulation of cardiac muscle cell apoptotic process • positive regulation of cell-substrate adhesion • positive regulation of phosphatidylinositol 3-kinase signaling • cell migration • peptidyl-tyrosine phosphorylation • cytokine-mediated signaling pathway • negative regulation of cell-cell adhesion • actin filament polymerization • cell differentiation • erythrocyte differentiation • positive regulation of cell migration • axon regeneration • mineralocorticoid receptor signaling pathway • positive regulation of insulin secretion • response to lipopolysaccharide • positive regulation of phosphoprotein phosphatase activity • positive regulation of interleukin-1 beta production • positive regulation of tumor necrosis factor production • positive regulation of protein import into nucleus, translocation • response to hydroperoxide • tumor necrosis factor-mediated signaling pathway • host programmed cell death induced by symbiont • response to tumor necrosis factor • histone H3-Y41 phosphorylation • intracellular signal transduction • interleukin-12-mediated signaling pathway • peptidyl-tyrosine autophosphorylation • regulation of cell proliferation • tyrosine phosphorylation of Stat3 protein • tyrosine phosphorylation of Stat5 protein • tyrosine phosphorylation of Stat1 protein • positive regulation of tyrosine phosphorylation of Stat3 protein • positive regulation of tyrosine phosphorylation of Stat5 protein • activation of JAK2 kinase activity • regulation of apoptotic process • positive regulation of DNA binding • negative regulation of DNA binding • negative regulation of neuron apoptotic process • innate immune response • positive regulation of nitric oxide biosynthetic process • positive regulation of cell differentiation • negative regulation of heart contraction • positive regulation of transcription from RNA polymerase II promoter • response to antibiotic • protein autophosphorylation • platelet-derived growth factor receptor signaling pathway • regulation of inflammatory response • positive regulation of inflammatory response • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of cell activation • positive regulation of sequence-specific DNA binding transcription factor activity • positive regulation of nitric-oxide synthase biosynthetic process • interferon-gamma-mediated signaling pathway • regulation of interferon-gamma-mediated signaling pathway • growth hormone receptor signaling pathway • JAK-STAT cascade involved in growth hormone signaling pathway • positive regulation of growth hormone receptor signaling pathway • mammary gland epithelium development • response to interleukin-12 • cellular response to lipopolysaccharide • cellular response to dexamethasone stimulus • extrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3717	16452
Ensembl	ENSG00000096968	ENSMUSG00000024789
UniProt	O60674	Q62120
RefSeq (mRNA)	NM_004972	NM_001048177
RefSeq (protein)	NP_004963	NP_001041642
Location (UCSC)	Chr 9: 4.99 – 5.13 Mb	Chr 19: 29.25 – 29.31 Mb
PubMed search

Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and 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). JAK2 signaling is activated downstream from the prolactin receptor.^[1]

The distinguishing feature between janus kinase 2 and other JAK kinases is the lack of Src homology binding domains (SH2/SH3) and the presence of up to seven JAK homology domains (JH1-JH7). Nonetheless the terminal JH domains retain a high level of homology to tyrosine kinase domains. An interesting note is that only one of these carboxy-terminal JH domains retains its function whilst the other, due to lacking important amino acids for kinase functionality, does not work; it is therefore termed as the pseudokinase domain.^[2]

Loss of Jak2 is lethal by embryonic day 12 in mice.^[3]

JAK2 orthologs ^[4] have been identified in all mammals for which complete genome data are available.

Clinical significance

JAK2 gene fusions with the TEL(ETV6) (TEL-JAK2) and PCM1 genes have been found in leukemia patients.^[5][6] Jak - 2 kinase mutations were found to have a high correlation with abnormal heart defects in those of Southeast Asian descent carrying the PYFA gene.^[5][6]

Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders.^[7] This mutation (V617F), 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, because the receptors for these growth factors require JAK2 for signal transduction. An inhibitor of JAK2-STAT5, AZD1480, was pointed as having activity in primary and CRPC.^[8] Jak2 mutation, when demonstrable, is one of the methods of diagnosing Polycythemia rubra vera.^[9]

Interactions

Janus kinase 2 has been shown to interact with:

• DNAJA3,^[10]
• EGFR,^[11]
• EPOR,^[12][13]
• FYN,^[14]
• Grb2,^[15][16]
• GHR,^[17][18][19]
• IRS1,^[20][21]
• IL12RB2,^[22]
• IL5RA,^[23]
• PIK3R1,^[24]
• PPP2R4,^[24]
• PTK2,^[25][26]
• PTPN11,^[27][28][29]
• PTPN6,^[30][31]
• PRMT5,^[32]
• SH2B1,^[33][34]
• SHC1,^[35][36]
• SOCS3,^[37][38][39]
• STAT5A,^[40][41]
• STAT5B,^[40][41]
• STAM,^[42]
• SOCS1,^{[39][43][44][45][46][47]}
• TEC,^[48][49]
• TNFRSF1A,^[50]
• VAV1,^[51][52] and
• YES1.^[24]

Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.^[53]

See also

• Janus kinase inhibitor, medical drugs under development

References

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4. "OrthoMaM phylogenetic marker: JAK2 coding sequence".
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52. "Findings of scientific misconduct". NIH Guide Grants Contracts 24 (42): 1–2. 1995. PMID 7495607.
53. Helmer RA, Panchoo M, Dertien JS, Bhakta SM, Hewetson A, Chilton BS (August 2010). "Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling". Mol. Cell. Endocrinol. 325 (1-2): 143–9. doi:10.1016/j.mce.2010.05.010. PMC 2902710. PMID 20562009.

Further reading

• Berger R (2006). "[A recurrent mutation of the JAK2 gene in chronic myeloproliferative disorders]". Pathol. Biol. 54 (4): 182–4. doi:10.1016/j.patbio.2005.07.002. PMID 16084028.
• Pargade V, Darnige L, Gaussem P (2006). "[Acquired mutation of JAK2 tyrosine kinase and polycythaemia vera]". Ann. Biol. Clin. (Paris) 64 (1): 3–9. PMID 16420986.
• Staerk J, Kallin A, Royer Y, et al. (2007). "JAK2, the JAK2 V617F mutant and cytokine receptors". Pathol. Biol. 55 (2): 88–91. doi:10.1016/j.patbio.2006.06.003. PMID 16904848.
• Hsu HC (2007). "Pathogenetic role of JAK2 V617F mutation in chronic myeloproliferative disorders". Journal of the Chinese Medical Association : JCMA 70 (3): 89–93. doi:10.1016/S1726-4901(09)70337-5. PMID 17389152.

External links

• Janus Kinase 2 at the US National Library of Medicine Medical Subject Headings (MeSH)