Biology:Janus kinase 2

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Short description: Non-receptor tyrosine kinase and coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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).[1][2]

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.[3][4]

Loss of Jak2 is lethal by embryonic day 12 in mice.[5]

JAK2 orthologs[6] 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.[7][8][9]

Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders.[10] 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.[11]

Interactions

Janus kinase 2 has been shown to interact with:


Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.[55]

See also

  • Janus kinase inhibitor, medical drugs under development
  • Ruxolitinib

References

  1. ↑ "Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice". Endocrine Reviews 19 (3): 225–68. June 1998. doi:10.1210/edrv.19.3.0334. PMID 9626554. 
  2. ↑ "Mechanism of activation of protein kinase JAK2 by the growth hormone receptor". Science 344 (6185): 1249783. 2014. doi:10.1126/science.1249783. PMID 24833397. 
  3. ↑ "A role for JAK2 mutations in myeloproliferative diseases". Annual Review of Medicine 59 (1): 213–22. 2008. doi:10.1146/annurev.med.59.061506.154159. PMID 17919086. 
  4. ↑ "The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling". Nature Structural & Molecular Biology 18 (9): 971–976. August 2011. doi:10.1038/nsmb.2099. PMID 21841788. 
  5. ↑ "Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis". Cell 93 (3): 397–409. May 1998. doi:10.1016/S0092-8674(00)81168-X. PMID 9590174. 
  6. ↑ "OrthoMaM phylogenetic marker: JAK2 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000096968_JAK2.xml. [yes|permanent dead link|dead link}}]
  7. ↑ "A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia". Science 278 (5341): 1309–12. November 1997. doi:10.1126/science.278.5341.1309. PMID 9360930. Bibcode: 1997Sci...278.1309L. 
  8. ↑ "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. April 2005. doi:10.1158/0008-5472.CAN-04-4263. PMID 15805263. 
  9. ↑ "Myeloid neoplasms with eosinophilia". Blood 129 (6): 704–714. 2017. doi:10.1182/blood-2016-10-695973. PMID 28028030. 
  10. ↑ "A gain-of-function mutation of JAK2 in myeloproliferative disorders". The New England Journal of Medicine 352 (17): 1779–90. April 2005. doi:10.1056/NEJMoa051113. PMID 15858187. 
  11. ↑ "The JAK2 exon 12 mutations: a comprehensive review". American Journal of Hematology 86 (8): 668–76. August 2011. doi:10.1002/ajh.22063. PMID 21674578. 
  12. ↑ "hTid-1, a human DnaJ protein, modulates the interferon signaling pathway". The Journal of Biological Chemistry 276 (52): 49034–42. December 2001. doi:10.1074/jbc.M103683200. PMID 11679576. 
  13. ↑ "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry 274 (24): 17209–18. June 1999. doi:10.1074/jbc.274.24.17209. PMID 10358079. 
  14. ↑ "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. December 2001. doi:10.1016/S1097-2765(01)00401-4. PMID 11779507. 
  15. ↑ "JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin". Cell 74 (2): 227–36. July 1993. doi:10.1016/0092-8674(93)90414-L. PMID 8343951. 
  16. ↑ "A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn". The Journal of Biological Chemistry 274 (46): 33131–42. November 1999. doi:10.1074/jbc.274.46.33131. PMID 10551884. 
  17. ↑ "Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells". The Journal of Experimental Medicine 182 (6): 1801–6. December 1995. doi:10.1084/jem.182.6.1801. PMID 7500025. 
  18. ↑ "Involvement of Janus kinases in the insulin signaling pathway". European Journal of Biochemistry 234 (2): 656–60. December 1995. doi:10.1111/j.1432-1033.1995.656_b.x. PMID 8536716. 
  19. ↑ "Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor". The Journal of Biological Chemistry 270 (24): 14776–85. June 1995. doi:10.1074/jbc.270.24.14776. PMID 7540178. 
  20. ↑ "Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase". The Journal of Biological Chemistry 269 (34): 21709–17. August 1994. doi:10.1016/S0021-9258(17)31863-X. PMID 8063815. 
  21. ↑ "The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver". Growth Hormone & IGF Research 9 (3): 212–8. June 1999. doi:10.1054/ghir.1999.0111. PMID 10502458. 
  22. ↑ "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. March 1998. doi:10.1210/endo.139.3.5829. PMID 9492017. 
  23. ↑ "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. January 2001. doi:10.1084/jem.193.2.263. PMID 11208867. 
  24. ↑ "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. April 1999. doi:10.1006/bbrc.1999.0479. PMID 10198225. 
  25. ↑ "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. April 1998. doi:10.1182/blood.V91.7.2264. PMID 9516124. 
  26. ↑ 26.0 26.1 26.2 "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. July 1996. doi:10.1006/bbrc.1996.1023. PMID 8702385. 
  27. ↑ "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. April 1998. doi:10.1074/jbc.273.17.10682. PMID 9553131. 
  28. ↑ "Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125FAK, and paxillin". Journal of Immunology 165 (4): 2116–23. August 2000. doi:10.4049/jimmunol.165.4.2116. PMID 10925297. 
  29. ↑ "Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases". The Journal of Biological Chemistry 272 (2): 1032–7. January 1997. doi:10.1074/jbc.272.2.1032. PMID 8995399. 
  30. ↑ "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. June 1996. doi:10.1182/blood.V87.11.4495.bloodjournal87114495. PMID 8639815. 
  31. ↑ "SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates". Biochemical and Biophysical Research Communications 228 (1): 122–7. November 1996. doi:10.1006/bbrc.1996.1626. PMID 8912646. 
  32. ↑ "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. December 1996. doi:10.1128/mcb.16.12.6985. PMID 8943354. 
  33. ↑ "SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells". Blood Cells, Molecules & Diseases 26 (1): 15–24. February 2000. doi:10.1006/bcmd.2000.0273. PMID 10772872. 
  34. ↑ "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. October 1999. doi:10.1074/jbc.274.44.31531. PMID 10531356. 
  35. ↑ "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. November 1997. doi:10.1128/mcb.17.11.6633. PMID 9343427. 
  36. ↑ "Jak2 is involved in c-Myc induction by Bcr-Abl". Oncogene 21 (47): 7137–46. October 2002. doi:10.1038/sj.onc.1205942. PMID 12370803. 
  37. ↑ "Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2". The Journal of Biological Chemistry 270 (13): 7587–93. March 1995. doi:10.1074/jbc.270.13.7587. PMID 7535773. 
  38. ↑ "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase". Journal of Immunology 158 (9): 4097–103. May 1997. doi:10.4049/jimmunol.158.9.4097. PMID 9126968. 
  39. ↑ "CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2". The Journal of Biological Chemistry 275 (38): 29338–47. September 2000. doi:10.1074/jbc.M003456200. PMID 10882725. 
  40. ↑ "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. June 1999. doi:10.1046/j.1365-2443.1999.00263.x. PMID 10421843. 
  41. ↑ 41.0 41.1 "Cloning and characterization of novel CIS family genes". Biochemical and Biophysical Research Communications 239 (2): 439–46. October 1997. doi:10.1006/bbrc.1997.7484. PMID 9344848. 
  42. ↑ 42.0 42.1 "Jak2-Stat5 interactions analyzed in yeast". The Journal of Biological Chemistry 273 (20): 12567–75. May 1998. doi:10.1074/jbc.273.20.12567. PMID 9575217. 
  43. ↑ 43.0 43.1 "An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT". Oncogene 14 (7): 751–61. February 1997. doi:10.1038/sj.onc.1200907. PMID 9047382. 
  44. ↑ "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. April 1997. doi:10.1016/S1074-7613(00)80288-5. PMID 9133424. 
  45. ↑ "The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop". The EMBO Journal 18 (5): 1309–20. March 1999. doi:10.1093/emboj/18.5.1309. PMID 10064597. 
  46. ↑ "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology 142 (12): 5286–93. December 2001. doi:10.1210/endo.142.12.8549. PMID 11713228. 
  47. ↑ "A new protein containing an SH2 domain that inhibits JAK kinases". Nature 387 (6636): 921–4. June 1997. doi:10.1038/43213. PMID 9202126. Bibcode: 1997Natur.387..921E. 
  48. ↑ "Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling". The Journal of Biological Chemistry 274 (35): 24497–502. August 1999. doi:10.1074/jbc.274.35.24497. PMID 10455112. 
  49. ↑ "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. May 2002. doi:10.1128/MCB.22.10.3316-3326.2002. PMID 11971965. 
  50. ↑ "Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK". Oncogene 14 (19): 2273–82. May 1997. doi:10.1038/sj.onc.1201071. PMID 9178903. 
  51. ↑ "Tec and Jak2 kinases cooperate to mediate cytokine-driven activation of c-fos transcription". Blood 91 (5): 1496–507. March 1998. doi:10.1182/blood.V91.5.1496. PMID 9473212. 
  52. ↑ "Induction of Jak/STAT signaling by activation of the type 1 TNF receptor". Journal of Immunology 160 (6): 2742–50. March 1998. doi:10.4049/jimmunol.160.6.2742. PMID 9510175. 
  53. ↑ "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. May 1997. doi:10.1074/jbc.272.22.14334. PMID 9162069. 
  54. ↑ "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. January 1995. doi:10.1002/j.1460-2075.1995.tb06999.x. PMID 7530656. 
  55. ↑ "Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling". Molecular and Cellular Endocrinology 325 (1–2): 143–9. August 2010. doi:10.1016/j.mce.2010.05.010. PMID 20562009. 

Further reading

External links



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