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]
Quick Facts JAK2, Available structures ...
JAK2 |
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Available structures |
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PDB | Ortholog search: PDBe RCSB |
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List of PDB id codes |
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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 |
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Identifiers |
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Aliases | JAK2, JTK10, THCYT3, Janus kinase 2, MAX2 |
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External IDs | OMIM: 147796; MGI: 96629; HomoloGene: 21033; GeneCards: JAK2; OMA:JAK2 - orthologs |
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Wikidata |
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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.
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]
Janus kinase 2 has been shown to interact with:
Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.[59]
Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, Xu CF, Neubert TA, Skoda RC, Hubbard SR, Silvennoinen O (August 2011). "The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling". Nature Structural & Molecular Biology. 18 (9): 971–976. doi:10.1038/nsmb.2099. PMC 4504201. PMID 21841788.
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffé M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA (November 1997). "A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia". Science. 278 (5341): 1309–12. Bibcode:1997Sci...278.1309L. doi:10.1126/science.278.5341.1309. PMID 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 (April 2005). "The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2". Cancer Research. 65 (7): 2662–7. doi:10.1158/0008-5472.CAN-04-4263. PMID 15805263.
Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN (July 1993). "JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin". Cell. 74 (2): 227–36. doi:10.1016/0092-8674(93)90414-L. PMID 8343951. S2CID 37503350.
Hellgren G, Jansson JO, Carlsson LM, Carlsson B (June 1999). "The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver". Growth Hormone & IGF Research. 9 (3): 212–8. doi:10.1054/ghir.1999.0111. PMID 10502458.
Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T (January 2001). "Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation". The Journal of Experimental Medicine. 193 (2): 263–9. doi:10.1084/jem.193.2.263. PMC 2193341. PMID 11208867.
Yamamoto K, Shibata F, Miura O, Kamiyama R, Hirosawa S, Miyasaka N (April 1999). "Physical interaction between interleukin-12 receptor beta 2 subunit and Jak2 tyrosine kinase: Jak2 associates with cytoplasmic membrane-proximal region of interleukin-12 receptor beta 2 via amino-terminus". Biochemical and Biophysical Research Communications. 257 (2): 400–4. doi:10.1006/bbrc.1999.0479. PMID 10198225.
Fuhrer DK, Yang YC (July 1996). "Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11". Biochemical and Biophysical Research Communications. 224 (2): 289–96. doi:10.1006/bbrc.1996.1023. PMID 8702385.
Maegawa H, Kashiwagi A, Fujita T, Ugi S, Hasegawa M, Obata T, Nishio Y, Kojima H, Hidaka H, Kikkawa R (November 1996). "SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates". Biochemical and Biophysical Research Communications. 228 (1): 122–7. doi:10.1006/bbrc.1996.1626. PMID 8912646.
Wu DW, Stark KC, Dunnington D, Dillon SB, Yi T, Jones C, Pelus LM (February 2000). "SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells". Blood Cells, Molecules & Diseases. 26 (1): 15–24. doi:10.1006/bcmd.2000.0273. PMID 10772872.
Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, Yokouchi M, Ohtsubo M, Yoshimura A (October 1997). "Cloning and characterization of novel CIS family genes". Biochemical and Biophysical Research Communications. 239 (2): 439–46. doi:10.1006/bbrc.1997.7484. PMID 9344848.
Takeshita T, Arita T, Higuchi M, Asao H, Endo K, Kuroda H, Tanaka N, Murata K, Ishii N, Sugamura K (April 1997). "STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction". Immunity. 6 (4): 449–57. doi:10.1016/S1074-7613(00)80288-5. PMID 9133424.
Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A (March 1999). "The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop". The EMBO Journal. 18 (5): 1309–20. doi:10.1093/emboj/18.5.1309. PMC 1171221. PMID 10064597.
Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A (June 1997). "A new protein containing an SH2 domain that inhibits JAK kinases". Nature. 387 (6636): 921–4. Bibcode:1997Natur.387..921E. doi:10.1038/43213. PMID 9202126. S2CID 4347361.
Yamashita Y, Watanabe S, Miyazato A, Ohya Ki, Ikeda U, Shimada K, Komatsu N, Hatake K, Miura Y, Ozawa K, Mano H (March 1998). "Tec and Jak2 kinases cooperate to mediate cytokine-driven activation of c-fos transcription". Blood. 91 (5): 1496–507. doi:10.1182/blood.V91.5.1496. PMID 9473212.
- 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.
- Staerk J, Kallin A, Royer Y, Diaconu CC, Dusa A, Demoulin JB, Vainchenker W, Constantinescu SN (March 2007). "JAK2, the JAK2 V617F mutant and cytokine receptors". Pathologie-Biologie. 55 (2): 88–91. doi:10.1016/j.patbio.2006.06.003. PMID 16904848.
- Hsu HC (March 2007). "Pathogenetic role of JAK2 V617F mutation in chronic myeloproliferative disorders". Journal of the Chinese Medical Association. 70 (3): 89–93. doi:10.1016/S1726-4901(09)70337-5. PMID 17389152. S2CID 33300937.