Janus kinase 2

JAK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5AEP, 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, 4YTC, 4YTF, 4YTH, 4YTI, 5CF4, 5CF5, 5CF6, 5CF8, 5I4N, 4Z32, 5L3A
Identifiers
Aliases	JAK2, JTK10, THCYT3, Janus kinase 2, MAX2
External IDs	OMIM: 147796; MGI: 96629; HomoloGene: 21033; GeneCards: JAK2; OMA:JAK2 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p24.1 Start 4,984,390 bp[1] End 5,129,948 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 C1|19 23.73 cM Start 29,229,228 bp[2] End 29,290,480 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon monocyte popliteal artery tibial arteries glutes Descending thoracic aorta ascending aorta sural nerve tibia left coronary artery Top expressed in zygote secondary oocyte primary oocyte blood Paneth cell jejunum uterus Rostral migratory stream fossa mesenteric lymph nodes More reference expression data BioGPS n/a
Gene ontology Molecular function SH2 domain binding kinase activity signaling receptor binding ATP binding growth hormone receptor binding interleukin-12 receptor binding metal ion binding heme binding histone kinase activity (H3-Y41 specific) transferase activity histone binding protein binding protein tyrosine kinase activity protein kinase binding nucleotide binding non-membrane spanning protein tyrosine kinase activity identical protein binding protein kinase activity protein C-terminus binding type 1 angiotensin receptor binding acetylcholine receptor binding phosphatidylinositol 3-kinase binding insulin receptor substrate binding peptide hormone receptor binding Cellular component cytoplasm cytosol membrane extrinsic component of cytoplasmic side of plasma membrane caveola cytoskeleton nucleus nuclear matrix endosome lumen membrane raft endomembrane system nucleoplasm plasma membrane focal adhesion postsynapse glutamatergic synapse Biological process negative regulation of neuron apoptotic process intrinsic apoptotic signaling pathway in response to oxidative stress adaptive immune response interferon-gamma-mediated signaling pathway negative regulation of DNA binding tumor necrosis factor-mediated signaling pathway protein phosphorylation positive regulation of phosphoprotein phosphatase activity growth hormone receptor signaling pathway positive regulation of interleukin-1 beta production positive regulation of DNA binding mesoderm development activation of cysteine-type endopeptidase activity involved in apoptotic process negative regulation of cell population proliferation apoptotic process regulation of apoptotic process positive regulation of cell activation mammary gland epithelium development extrinsic apoptotic signaling pathway axon regeneration activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway response to antibiotic positive regulation of nitric-oxide synthase biosynthetic process response to oxidative stress response to tumor necrosis factor response to interleukin-12 positive regulation of cell differentiation positive regulation of tumor necrosis factor production positive regulation of peptidyl-tyrosine phosphorylation erythrocyte differentiation protein autophosphorylation platelet-derived growth factor receptor signaling pathway positive regulation of cell-substrate adhesion positive regulation of growth hormone receptor signaling pathway G protein-coupled receptor signaling pathway cell differentiation growth hormone receptor signaling pathway via JAK-STAT positive regulation of inflammatory response phosphorylation immune system process positive regulation of DNA-binding transcription factor activity negative regulation of cardiac muscle cell apoptotic process actin filament polymerization response to lipopolysaccharide regulation of inflammatory response peptidyl-tyrosine autophosphorylation enzyme linked receptor protein signaling pathway positive regulation of insulin secretion receptor signaling pathway via JAK-STAT intracellular signal transduction negative regulation of cell-cell adhesion mineralocorticoid receptor signaling pathway negative regulation of heart contraction positive regulation of cell migration positive regulation of cytosolic calcium ion concentration positive regulation of nitric oxide biosynthetic process blood coagulation response to hydroperoxide MAPK cascade regulation of interferon-gamma-mediated signaling pathway regulation of cell population proliferation positive regulation of cell population proliferation hormone-mediated signaling pathway positive regulation of apoptotic process positive regulation of phosphatidylinositol 3-kinase signaling peptidyl-tyrosine phosphorylation cell migration signal transduction positive regulation of epithelial cell apoptotic process positive regulation of growth factor dependent skeletal muscle satellite cell proliferation innate immune response negative regulation of cell death positive regulation of vascular associated smooth muscle cell proliferation positive regulation of tyrosine phosphorylation of STAT protein activation of Janus kinase activity tyrosine phosphorylation of STAT protein interleukin-12-mediated signaling pathway cytokine-mediated signaling pathway interleukin-23-mediated signaling pathway interleukin-6-mediated signaling pathway interleukin-27-mediated signaling pathway interleukin-35-mediated signaling pathway chromatin organization regulation of receptor signaling pathway via JAK-STAT regulation of nitric oxide biosynthetic process positive regulation of Ras protein signal transduction modulation of chemical synaptic transmission postsynapse to nucleus signaling pathway positive regulation of cold-induced thermogenesis microglial cell activation positive regulation of MHC class II biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3717 16452 Ensembl ENSG00000096968 ENSMUSG00000024789 UniProt O60674 Q62120 RefSeq (mRNA) NM_004972 NM_001322194 NM_001322195 NM_001322196 NM_001322198 NM_001322199 NM_001322204 NM_001048177 NM_008413 RefSeq (protein) NP_001309123 NP_001309124 NP_001309125 NP_001309127 NP_001309128 NP_001309133 NP_004963 NP_001041642 NP_032439 Location (UCSC) Chr 9: 4.98 – 5.13 Mb Chr 19: 29.23 – 29.29 Mb PubMed search [3] [4]
Wikidata
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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).^[5][6]

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 full kinase function (JH1) while the other (JH2), previously thought to have no kinase functionality and accordingly termed a pseudokinase domain, has since been found to be catalytically active, albeit at only 10% that of the JH1 domain.^[7][8]

Loss of JAK2 is lethal by embryonic day 12 in mice.^[9]

JAK2 orthologs^[10] 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 patients suffering leukemia, particularly clonal eosinophilia forms of the disease.^[11][12][13]

Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders.^[14] 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. JAK2 mutation, when demonstrable, is one of the methods of diagnosing polycythemia vera.^[15]

Interactions

Janus kinase 2 has been shown to interact with:

• DNAJA3^[16]
• EGFR^[17]
• EPOR^[18][19]
• FYN^[20]
• Grb2^[21][22]
• GHR^[23][24][25]
• IRS1^[26][27]
• IL12RB2^[28]
• IL5RA^[29]
• PIK3R1^[30]
• PPP2R4^[30]
• PTK2^[31][32]
• PTPN11^[33][34][35]
• PTPN6^[36][37]
• PRMT5^[38]
• SH2B1^[39][40]
• SHC1^[41][42]
• SOCS3^[43][44][45]
• STAT5A^[46][47]
• STAT5B^[46][47]
• STAM^[48]
• SOCS1^{[45][49][50][51][52][53]}
• TEC^[54][55]
• TNFRSF1A^[56]
• VAV1^[57][58]
• YES1^[30]

Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.^[59]

See also

• Janus kinase inhibitor, medical drugs under development
• Ruxolitinib

References

1. GRCh38: Ensembl release 89: ENSG00000096968 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024789 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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6. Brooks AJ, Dai W, O'Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, et al. (2014). "Mechanism of activation of protein kinase JAK2 by the growth hormone receptor". Science. 344 (6185): 1249783. doi:10.1126/science.1249783. PMID 24833397. S2CID 27946074.
7. Morgan KJ, Gilliland DG (2008). "A role for JAK2 mutations in myeloproliferative diseases". Annual Review of Medicine. 59 (1): 213–22. doi:10.1146/annurev.med.59.061506.154159. PMID 17919086.
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58. Matsuguchi T, Inhorn RC, Carlesso N, Xu G, Druker B, Griffin JD (January 1995). "Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL". EMBO J. 14 (2): 257–65. doi:10.1002/j.1460-2075.1995.tb06999.x. PMC 398079. PMID 7530656.
59. 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". Molecular and Cellular Endocrinology. 325 (1–2): 143–9. doi:10.1016/j.mce.2010.05.010. PMC 2902710. PMID 20562009.

Further reading

• Berger R (May 2006). "[A recurrent mutation of the JAK2 gene in chronic myeloproliferative disorders]". Pathologie-Biologie. 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]". Annales de Biologie Clinique. 64 (1): 3–9. PMID 16420986.
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External links

• Janus+Kinase+2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)