Janus kinase 2

JAK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases JAK2, JTK10, THCYT3, Janus kinase 2
External IDs OMIM: 147796 MGI: 96629 HomoloGene: 21033 GeneCards: JAK2
Genetically Related Diseases
Crohn's disease, myelodysplastic myeloproliferative cancer[1]
Targeted by Drug
Baricitinib, momelotinib, pacritinib, ruxolitinib, Baricitinib, momelotinib, pacritinib, ruxolitinib[2]
Orthologs
Species Human Mouse
Entrez

3717

16452

Ensembl

ENSG00000096968

ENSMUSG00000024789

UniProt

O60674

Q62120

RefSeq (mRNA)

NM_001048177
NM_008413

RefSeq (protein)

NP_001041642.1
NP_032439.2

Location (UCSC) Chr 9: 4.99 – 5.13 Mb Chr 19: 29.25 – 29.31 Mb
PubMed search [3] [4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

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 while the other, due to lacking important amino acids for kinase functionality, does not work; it is therefore termed as the pseudokinase domain.[6]

Loss of Jak2 is lethal by embryonic day 12 in mice.[7]

JAK2 orthologs [8] 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.[9][10] 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.[9][10]

Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders.[11] 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.[12] Jak2 mutation, when demonstrable, is one of the methods of diagnosing polycythemia vera.[13]

Interactions

Janus kinase 2 has been shown to interact with:

Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.[57]

See also

References

  1. ↑ "Diseases that are genetically associated with JAK2 view/edit references on wikidata".
  2. ↑ "Drugs that physically interact with Tyrosine-protein kinase JAK2 view/edit references on wikidata".
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA (June 1998). "Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice". Endocrine Reviews. 19 (3): 225–68. doi:10.1210/er.19.3.225. PMID 9626554.
  6. ↑ 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.
  7. ↑ Neubauer H, Cumano A, Müller M, Wu H, Huffstadt U, Pfeffer K (May 1998). "Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis". Cell. 93 (3): 397–409. doi:10.1016/S0092-8674(00)81168-X. PMID 9590174.
  8. ↑ "OrthoMaM phylogenetic marker: JAK2 coding sequence".
  9. 1 2 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. doi:10.1126/science.278.5341.1309. PMID 9360930.
  10. 1 2 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.
  11. ↑ Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (April 2005). "A gain-of-function mutation of JAK2 in myeloproliferative disorders". The New England Journal of Medicine. 352 (17): 1779–90. doi:10.1056/NEJMoa051113. PMID 15858187.
  12. ↑ Gu L, Liao Z, Hoang DT, Dagvadorj A, Gupta S, Blackmon S, Ellsworth E, Talati P, Leiby B, Zinda M, Lallas CD, Trabulsi EJ, McCue P, Gomella L, Huszar D, Nevalainen MT (October 2013). "Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer". Clinical Cancer Research. 19 (20): 5658–74. doi:10.1158/1078-0432.CCR-13-0422. PMID 23942095.
  13. ↑ Scott LM (August 2011). "The JAK2 exon 12 mutations: a comprehensive review". American Journal of Hematology. 86 (8): 668–76. doi:10.1002/ajh.22063. PMID 21674578.
  14. ↑ Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S (December 2001). "hTid-1, a human DnaJ protein, modulates the interferon signaling pathway". The Journal of Biological Chemistry. 276 (52): 49034–42. doi:10.1074/jbc.M103683200. PMID 11679576.
  15. ↑ Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (June 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry. 274 (24): 17209–18. doi:10.1074/jbc.274.24.17209. PMID 10358079.
  16. ↑ Huang LJ, Constantinescu SN, Lodish HF (December 2001). "The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor". Molecular Cell. 8 (6): 1327–38. doi:10.1016/S1097-2765(01)00401-4. PMID 11779507.
  17. ↑ 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.
  18. ↑ Sayeski PP, Ali MS, Safavi A, Lyles M, Kim SO, Frank SJ, Bernstein KE (November 1999). "A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn". The Journal of Biological Chemistry. 274 (46): 33131–42. doi:10.1074/jbc.274.46.33131. PMID 10551884.
  19. ↑ Chauhan D, Kharbanda SM, Ogata A, Urashima M, Frank D, Malik N, Kufe DW, Anderson KC (December 1995). "Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells". The Journal of Experimental Medicine. 182 (6): 1801–6. doi:10.1084/jem.182.6.1801. PMC 2192257Freely accessible. PMID 7500025.
  20. ↑ Giorgetti-Peraldi S, Peyrade F, Baron V, Van Obberghen E (December 1995). "Involvement of Janus kinases in the insulin signaling pathway". European Journal of Biochemistry / FEBS. 234 (2): 656–60. doi:10.1111/j.1432-1033.1995.656_b.x. PMID 8536716.
  21. ↑ Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS (June 1995). "Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor". The Journal of Biological Chemistry. 270 (24): 14776–85. doi:10.1074/jbc.270.24.14776. PMID 7540178.
  22. ↑ VanderKuur JA, Wang X, Zhang L, Campbell GS, Allevato G, Billestrup N, Norstedt G, Carter-Su C (August 1994). "Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase". The Journal of Biological Chemistry. 269 (34): 21709–17. PMID 8063815.
  23. ↑ 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.
  24. ↑ Gual P, Baron V, Lequoy V, Van Obberghen E (March 1998). "Interaction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-1 receptor". Endocrinology. 139 (3): 884–93. doi:10.1210/endo.139.3.5829. PMID 9492017.
  25. ↑ 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 2193341Freely accessible. PMID 11208867.
  26. ↑ 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.
  27. ↑ Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T, Takatsu K (April 1998). "JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation". Blood. 91 (7): 2264–71. PMID 9516124.
  28. 1 2 3 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.
  29. ↑ Zhu T, Goh EL, Lobie PE (April 1998). "Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription". The Journal of Biological Chemistry. 273 (17): 10682–9. doi:10.1074/jbc.273.17.10682. PMID 9553131.
  30. ↑ Ryu H, Lee JH, Kim KS, Jeong SM, Kim PH, Chung HT (August 2000). "Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125FAK, and paxillin". Journal of Immunology. 165 (4): 2116–23. doi:10.4049/jimmunol.165.4.2116. PMID 10925297.
  31. ↑ Yin T, Shen R, Feng GS, Yang YC (January 1997). "Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases". The Journal of Biological Chemistry. 272 (2): 1032–7. doi:10.1074/jbc.272.2.1032. PMID 8995399.
  32. ↑ Tauchi T, Damen JE, Toyama K, Feng GS, Broxmeyer HE, Krystal G (June 1996). "Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis". Blood. 87 (11): 4495–501. PMID 8639815.
  33. ↑ 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.
  34. ↑ Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T (December 1996). "Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1". Molecular and Cellular Biology. 16 (12): 6985–92. PMC 231702Freely accessible. PMID 8943354.
  35. ↑ 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.
  36. ↑ Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S (October 1999). "The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity". The Journal of Biological Chemistry. 274 (44): 31531–42. doi:10.1074/jbc.274.44.31531. PMID 10531356.
  37. ↑ Rui L, Mathews LS, Hotta K, Gustafson TA, Carter-Su C (November 1997). "Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling". Molecular and Cellular Biology. 17 (11): 6633–44. PMC 232517Freely accessible. PMID 9343427.
  38. ↑ Xie S, Lin H, Sun T, Arlinghaus RB (October 2002). "Jak2 is involved in c-Myc induction by Bcr-Abl". Oncogene. 21 (47): 7137–46. doi:10.1038/sj.onc.1205942. PMID 12370803.
  39. ↑ VanderKuur J, Allevato G, Billestrup N, Norstedt G, Carter-Su C (March 1995). "Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2". The Journal of Biological Chemistry. 270 (13): 7587–93. doi:10.1074/jbc.270.13.7587. PMID 7535773.
  40. ↑ Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, Gadina M, Scala G (May 1997). "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase". Journal of Immunology. 158 (9): 4097–103. PMID 9126968.
  41. ↑ Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A (September 2000). "CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2". The Journal of Biological Chemistry. 275 (38): 29338–47. doi:10.1074/jbc.M003456200. PMID 10882725.
  42. ↑ Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A (June 1999). "Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain". Genes to Cells. 4 (6): 339–51. doi:10.1046/j.1365-2443.1999.00263.x. PMID 10421843.
  43. 1 2 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.
  44. 1 2 Barahmand-Pour F, Meinke A, Groner B, Decker T (May 1998). "Jak2-Stat5 interactions analyzed in yeast". The Journal of Biological Chemistry. 273 (20): 12567–75. doi:10.1074/jbc.273.20.12567. PMID 9575217.
  45. 1 2 Fujitani Y, Hibi M, Fukada T, Takahashi-Tezuka M, Yoshida H, Yamaguchi T, Sugiyama K, Yamanaka Y, Nakajima K, Hirano T (February 1997). "An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT". Oncogene. 14 (7): 751–61. doi:10.1038/sj.onc.1200907. PMID 9047382.
  46. ↑ 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.
  47. ↑ 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 1171221Freely accessible. PMID 10064597.
  48. ↑ Dif F, Saunier E, Demeneix B, Kelly PA, Edery M (December 2001). "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology. 142 (12): 5286–93. doi:10.1210/endo.142.12.8549. PMID 11713228.
  49. ↑ 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. doi:10.1038/43213. PMID 9202126.
  50. ↑ Pezet A, Favre H, Kelly PA, Edery M (August 1999). "Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling". The Journal of Biological Chemistry. 274 (35): 24497–502. doi:10.1074/jbc.274.35.24497. PMID 10455112.
  51. ↑ Ungureanu D, Saharinen P, Junttila I, Hilton DJ, Silvennoinen O (May 2002). "Regulation of Jak2 through the ubiquitin-proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1". Molecular and Cellular Biology. 22 (10): 3316–26. doi:10.1128/MCB.22.10.3316-3326.2002. PMC 133778Freely accessible. PMID 11971965.
  52. ↑ Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T (May 1997). "Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK". Oncogene. 14 (19): 2273–82. doi:10.1038/sj.onc.1201071. PMID 9178903.
  53. ↑ 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. PMID 9473212.
  54. ↑ Guo D, Dunbar JD, Yang CH, Pfeffer LM, Donner DB (March 1998). "Induction of Jak/STAT signaling by activation of the type 1 TNF receptor". Journal of Immunology. 160 (6): 2742–50. PMID 9510175.
  55. ↑ Shigematsu H, Iwasaki H, Otsuka T, Ohno Y, Arima F, Niho Y (May 1997). "Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity". The Journal of Biological Chemistry. 272 (22): 14334–40. doi:10.1074/jbc.272.22.14334. PMID 9162069.
  56. ↑ "Findings of scientific misconduct". NIH Guide for Grants and Contracts / U.S. Department of Health, Education, and Welfare. 24 (42): 1–2. December 1995. PMID 7495607.
  57. ↑ 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 2902710Freely accessible. 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. 
  • 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. 
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