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Gene Review

JAK2  -  Janus kinase 2

Homo sapiens

Synonyms: JAK-2, JTK10, THCYT3, Tyrosine-protein kinase JAK2
 Grimley, Margherita Massa, Giorgina Specchia, Mario Lazzarino, Alessandro M. Vannucchi, Roberto Marchioli,  Leong,  Choudhury, Alessandro Rambaldi,  Ballesteros,  Löwenberg, Monia Marchetti, Ester Pungolino, Paola Guglielmelli, Cristiana Pascutto,  Lobie,  Dong, Alessandro M. Vannucchi, Alessandro Rambaldi, Paola Guglielmelli, Giovanni Barosi,  Ronsin, Giorgina Specchia,  Karras,  Fang, Rita Campanelli,  Jove,  Ghosh-Choudhury, Enrica Morra, Fabrizio Fabris, Gianluca Viarengo,  Huang,  Pegoraro,  von Lindern, Margherita Scapin,  Mehta,  Deiner, Rosa Maria Marfisi, Elisa Rumi,  Morel, Guido Finazzi,  van Dijk, Chiara Elena, Remigio Moratti, Sabrina Caberlon,  Doyle,  Watts, Laura Villani, Mario Cazzola,  Rui,  Low,  Barton, Vittoria Guerini, Luca Arcaini, Gaetano Bergamaschi, Francesco Passamonti,  Murphy,  Dentelli,  Norstedt,  Tarone, Maria Luigia Randi, Vittorio Rosti,  Barton,  Willems,  Leung, Vincenzo Liso, Valerio De Stefano, Elisabetta Antonioli, Tiziano Barbui, Elisabetta Antonioli, Luigi Gugliotta,  Ho,  Calvi, Fabrizio Fabris, Giovanni Barosi,  Williams, Daniela Pietra, Enrico Pogliani, Giancarla Gerli,  Brizzi, Elisabetta Gattoni,  Parren-van Amelsvoort,  van Emst-de Vries,  Sjogren,  Garbarino, Marco Ruggeri, Maria Luigia Randi,  Silvennoinen, Agostino Tafuri, Fabiana Tezza,  Defilippi,  Garcia,  Beug,  Liu, Tiziano Barbui, Carmine Tinelli,  Zuckerman,  Haldosén,  van den Akker,  Rosso, Edoardo Rossi,  Fan, Alberto Bosi,  Ross,  Xu,  Abboud,  
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Disease relevance of JAK2


High impact information on JAK2


Chemical compound and disease context of JAK2


Biological context of JAK2

  • The crystal structure of the extracellular domain of EPOR in its unliganded form at 2.4 angstrom resolution has revealed a dimer in which the individual membrane-spanning and intracellular domains would be too far apart to permit phosphorylation by JAK2 [23].
  • CONCLUSIONS: GH inhibits CCh-induced chloride secretion via a JAK2-dependent mechanism involving transactivation of EGFr and consequent recruitment of ERK1/2 [24].
  • E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression [25].
  • Taken together, these data indicate that JAK2 likely plays a key role in TPO-mediated signal transduction [26].
  • The carboxyl terminus of SH2-Bbeta (SH2-Bbetac), which contains the SH2 domain, specifically interacts with kinase-active, tyrosyl-phosphorylated JAK2 but not kinase-inactive, unphosphorylated JAK2 in the yeast two-hybrid system [27].

Anatomical context of JAK2


Associations of JAK2 with chemical compounds

  • Murine JAK2 has a total of 49 tyrosines which, if phosphorylated, could serve as docking sites for Src homology 2 (SH2) or phosphotyrosine binding domain-containing signaling molecules [27].
  • Detailed study of the C-terminal truncated cytoplasmic domain of hIL-5Ralpha revealed that the cytoplasmic stretch at position 346-387, containing the proline-rich region, is necessary for JAK2 binding [33].
  • These data suggest that phosphorylation of either serine or tyrosine residues of the EPOR can enhance the association of the receptor with JAK2, possibly increasing the sensitivity to EPO [34].
  • PKC inhibitors or LY294002 did not affect membrane expression of the EpoR, the association of JAK2 with the EpoR, or the in vitro kinase activity of JAK2 [35].
  • Verapamil inhibited neither [3H]thymidine incorporation nor JAK2 phosphorylation stimulated by hGH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect [36].

Physical interactions of JAK2

  • In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2 [37].
  • RESULTS: We showed that endogenous CIS3 bound to JAK2 in intact cells [38].
  • The signaling molecules that are recruited and activated by the GHR-JAK2 complex include signal transducers and activators of transcription (Stat) factors, the adapter protein Shc, and the insulin receptor substrates (IRSs) 1 and 2 [39].
  • Phosphorylated JAK2 was primarily bound to a short 106kDa leptin receptor isoform and to a lesser extent to a 210kDa molecule [40].
  • Only after 60 min of this treatment did we observe tyrosine phosphorylation of Jak2 and p91 and assembly of the transcription factor complex FcRF gamma that binds to the promoter of the fcgr1 gene [41].

Enzymatic interactions of JAK2


Regulatory relationships of JAK2


Other interactions of JAK2


Analytical, diagnostic and therapeutic context of JAK2

  • SH2-Bbetac also binds to immunoprecipitated wild-type but not kinase-inactive JAK2 in a far Western blot [27].
  • Hence, H-2g signals through JAK2 and its downstream signal transducers STAT3, Erk1/2, and phosphatidylinositol 3-kinase result in ICAM-1 expression and cell adhesion [54].
  • By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1 [55].
  • Identification of the proteins recruited to the GH receptor-JAK2 complex and dissection of the signaling pathways that are subsequently activated will ultimately provide a basis for understanding GH action at the molecular level [56].
  • Western blot analysis of purified nuclear extracts revealed the presence of immunoreactive JAK1 at 130 kDa and immunoreactive JAK2 at 128 kDa [57].


  1. TYK2 is a key regulator of the surveillance of B lymphoid tumors. Stoiber, D., Kovacic, B., Schuster, C., Schellack, C., Karaghiosoff, M., Kreibich, R., Weisz, E., Artwohl, M., Kleine, O.C., Muller, M., Baumgartner-Parzer, S., Ghysdael, J., Freissmuth, M., Sexl, V. J. Clin. Invest. (2004) [Pubmed]
  2. Tyrosine phosphorylation of p95Vav in myeloid cells is regulated by GM-CSF, IL-3 and steel factor and is constitutively increased by p210BCR/ABL. Matsuguchi, T., Inhorn, R.C., Carlesso, N., Xu, G., Druker, B., Griffin, J.D. EMBO J. (1995) [Pubmed]
  3. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Lu, X., Levine, R., Tong, W., Wernig, G., Pikman, Y., Zarnegar, S., Gilliland, D.G., Lodish, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Lacronique, V., Boureux, A., Monni, R., Dumon, S., Mauchauffé, M., Mayeux, P., Gouilleux, F., Berger, R., Gisselbrecht, S., Ghysdael, J., Bernard, O.A. Blood (2000) [Pubmed]
  5. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Peeters, P., Raynaud, S.D., Cools, J., Wlodarska, I., Grosgeorge, J., Philip, P., Monpoux, F., Van Rompaey, L., Baens, M., Van den Berghe, H., Marynen, P. Blood (1997) [Pubmed]
  6. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Pardanani, A., Lasho, T.L., Finke, C., Hanson, C.A., Tefferi, A. Leukemia (2007) [Pubmed]
  7. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Malinge, S., Ben-Abdelali, R., Settegrana, C., Radford-Weiss, I., Debre, M., Beldjord, K., Macintyre, E.A., Villeval, J.L., Vainchenker, W., Berger, R., Bernard, O.A., Delabesse, E., Penard-Lacronique, V. Blood (2007) [Pubmed]
  8. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Barosi, G., Bergamaschi, G., Marchetti, M., Vannucchi, A.M., Guglielmelli, P., Antonioli, E., Massa, M., Rosti, V., Campanelli, R., Villani, L., Viarengo, G., Gattoni, E., Gerli, G., Specchia, G., Tinelli, C., Rambaldi, A., Barbui, T. Blood (2007) [Pubmed]
  9. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Passamonti, F., Randi, M.L., Rumi, E., Pungolino, E., Elena, C., Pietra, D., Scapin, M., Arcaini, L., Tezza, F., Moratti, R., Pascutto, C., Fabris, F., Morra, E., Cazzola, M., Lazzarino, M. Blood (2007) [Pubmed]
  10. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Vannucchi, A.M., Antonioli, E., Guglielmelli, P., Rambaldi, A., Barosi, G., Marchioli, R., Marfisi, R.M., Finazzi, G., Guerini, V., Fabris, F., Randi, M.L., De Stefano, V., Caberlon, S., Tafuri, A., Ruggeri, M., Specchia, G., Liso, V., Rossi, E., Pogliani, E., Gugliotta, L., Bosi, A., Barbui, T. Blood (2007) [Pubmed]
  11. The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Dupont, S., Massé, A., James, C., Teyssandier, I., Lécluse, Y., Larbret, F., Ugo, V., Saulnier, P., Koscielny, S., Le Couédic, J.P., Casadevall, N., Vainchenker, W., Delhommeau, F. Blood (2007) [Pubmed]
  12. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Pietra, D., Li, S., Brisci, A., Passamonti, F., Rumi, E., Theocharides, A., Ferrari, M., Gisslinger, H., Kralovics, R., Cremonesi, L., Skoda, R., Cazzola, M. Blood (2008) [Pubmed]
  13. WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Verstovsek, S., Manshouri, T., Quintás-Cardama, A., Harris, D., Cortes, J., Giles, F.J., Kantarjian, H., Priebe, W., Estrov, Z. Clin. Cancer Res. (2008) [Pubmed]
  14. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Tiedt, R., Hao-Shen, H., Sobas, M.A., Looser, R., Dirnhofer, S., Schwaller, J., Skoda, R.C. Blood (2008) [Pubmed]
  15. Mechanism of signaling by growth hormone receptor. Argetsinger, L.S., Carter-Su, C. Physiol. Rev. (1996) [Pubmed]
  16. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Yoshikawa, H., Matsubara, K., Qian, G.S., Jackson, P., Groopman, J.D., Manning, J.E., Harris, C.C., Herman, J.G. Nat. Genet. (2001) [Pubmed]
  17. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Neubauer, H., Cumano, A., Müller, M., Wu, H., Huffstadt, U., Pfeffer, K. Cell (1998) [Pubmed]
  18. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines. Barton, B.E., Karras, J.G., Murphy, T.F., Barton, A., Huang, H.F. Mol. Cancer Ther. (2004) [Pubmed]
  19. Hyperglycemia activates JAK2 signaling pathway in human failing myocytes via angiotensin II-mediated oxidative stress. Modesti, A., Bertolozzi, I., Gamberi, T., Marchetta, M., Lumachi, C., Coppo, M., Moroni, F., Toscano, T., Lucchese, G., Gensini, G.F., Modesti, P.A. Diabetes (2005) [Pubmed]
  20. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. Scott, L.M., Tong, W., Levine, R.L., Scott, M.A., Beer, P.A., Stratton, M.R., Futreal, P.A., Erber, W.N., McMullin, M.F., Harrison, C.N., Warren, A.J., Gilliland, D.G., Lodish, H.F., Green, A.R. N. Engl. J. Med. (2007) [Pubmed]
  21. Activation of the Jak2-Stat5 signaling pathway in Nb2 lymphoma cells by an anti-apoptotic agent, aurintricarboxylic acid. Rui, H., Xu, J., Mehta, S., Fang, H., Williams, J., Dong, F., Grimley, P.M. J. Biol. Chem. (1998) [Pubmed]
  22. Chromosomal abnormalities and molecular markers in myeloproliferative disorders. Bench, A.J., Pahl, H.L. Semin. Hematol. (2005) [Pubmed]
  23. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Livnah, O., Stura, E.A., Middleton, S.A., Johnson, D.L., Jolliffe, L.K., Wilson, I.A. Science (1999) [Pubmed]
  24. Growth hormone reduces chloride secretion in human colonic epithelial cells via EGF receptor and extracellular regulated kinase. Chow, J.Y., Carlstrom, K., Barrett, K.E. Gastroenterology (2003) [Pubmed]
  25. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Leung, K.C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C.K., Low, T.H., Leong, G.M., Ross, R.J., Ho, K.K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  26. Thrombopoietin induces tyrosine phosphorylation and activation of the Janus kinase, JAK2. Tortolani, P.J., Johnston, J.A., Bacon, C.M., McVicar, D.W., Shimosaka, A., Linnekin, D., Longo, D.L., O'Shea, J.J. Blood (1995) [Pubmed]
  27. Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Rui, L., Mathews, L.S., Hotta, K., Gustafson, T.A., Carter-Su, C. Mol. Cell. Biol. (1997) [Pubmed]
  28. Association and direct activation of signal transducer and activator of transcription1alpha by platelet-derived growth factor receptor. Choudhury, G.G., Ghosh-Choudhury, N., Abboud, H.E. J. Clin. Invest. (1998) [Pubmed]
  29. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Bacon, C.M., Petricoin, E.F., Ortaldo, J.R., Rees, R.C., Larner, A.C., Johnston, J.A., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  30. Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. Liu, R.Y., Fan, C., Garcia, R., Jove, R., Zuckerman, K.S. Blood (1999) [Pubmed]
  31. Interleukin-5 signaling in human eosinophils involves JAK2 tyrosine kinase and Stat1 alpha. van der Bruggen, T., Caldenhoven, E., Kanters, D., Coffer, P., Raaijmakers, J.A., Lammers, J.W., Koenderman, L. Blood (1995) [Pubmed]
  32. Janus kinase 2 is involved in stromal cell-derived factor-1alpha-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. Zhang, X.F., Wang, J.F., Matczak, E., Proper, J.A., Groopman, J.E. Blood (2001) [Pubmed]
  33. JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation. Ogata, N., Kouro, T., Yamada, A., Koike, M., Hanai, N., Ishikawa, T., Takatsu, K. Blood (1998) [Pubmed]
  34. Association of JAK2 and STAT5 with erythropoietin receptors. Role of receptor phosphorylation in erythropoietin signal transduction. Sawyer, S.T., Penta, K. J. Biol. Chem. (1996) [Pubmed]
  35. Protein kinase C alpha controls erythropoietin receptor signaling. von Lindern, M., Parren-van Amelsvoort, M., van Dijk, T., Deiner, E., van den Akker, E., van Emst-de Vries, S., Willems, P., Beug, H., Löwenberg, B. J. Biol. Chem. (2000) [Pubmed]
  36. Postreceptor signalling of growth hormone and prolactin and their effects in the differentiated insulin-secreting cell line, INS-1. Sekine, N., Ullrich, S., Regazzi, R., Pralong, W.F., Wollheim, C.B. Endocrinology (1996) [Pubmed]
  37. SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Carter-Su, C., Rui, L., Stofega, M.R. Recent Prog. Horm. Res. (2000) [Pubmed]
  38. 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. Sasaki, A., Yasukawa, H., Suzuki, A., Kamizono, S., Syoda, T., Kinjyo, I., Sasaki, M., Johnston, J.A., Yoshimura, A. Genes Cells (1999) [Pubmed]
  39. Growth-hormone signal transduction. Campbell, G.S. J. Pediatr. (1997) [Pubmed]
  40. Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation. Caüzac, M., Czuba, D., Girard, J., Hauguel-de Mouzon, S. Placenta (2003) [Pubmed]
  41. Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. Igarashi, K., Garotta, G., Ozmen, L., Ziemiecki, A., Wilks, A.F., Harpur, A.G., Larner, A.C., Finbloom, D.S. J. Biol. Chem. (1994) [Pubmed]
  42. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. Gouilleux, F., Pallard, C., Dusanter-Fourt, I., Wakao, H., Haldosen, L.A., Norstedt, G., Levy, D., Groner, B. EMBO J. (1995) [Pubmed]
  43. The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. Vila-Coro, A.J., Rodríguez-Frade, J.M., Martín De Ana, A., Moreno-Ortíz, M.C., Martínez-A, C., Mellado, M. FASEB J. (1999) [Pubmed]
  44. Dissociation of Janus kinase 2 and signal transducer and activator of transcription 5 activation after treatment of Nb2 cells with a molecular mimic of phosphorylated prolactin. Coss, D., Kuo, C.B., Yang, L., Ingleton, P., Luben, R., Walker, A.M. Endocrinology (1999) [Pubmed]
  45. IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. Murata, T., Noguchi, P.D., Puri, R.K. J. Immunol. (1996) [Pubmed]
  46. Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Tian, S.S., Lamb, P., Seidel, H.M., Stein, R.B., Rosen, J. Blood (1994) [Pubmed]
  47. Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. Chauhan, D., Kharbanda, S.M., Ogata, A., Urashima, M., Frank, D., Malik, N., Kufe, D.W., Anderson, K.C. J. Exp. Med. (1995) [Pubmed]
  48. Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. Murata, T., Noguchi, P.D., Puri, R.K. J. Biol. Chem. (1995) [Pubmed]
  49. Cytokine-like effects of prolactin in human mononuclear and polymorphonuclear leukocytes. Dogusan, Z., Hooghe, R., Verdood, P., Hooghe-Peters, E.L. J. Neuroimmunol. (2001) [Pubmed]
  50. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Mohyeldin, A., Lu, H., Dalgard, C., Lai, S.Y., Cohen, N., Acs, G., Verma, A. Neoplasia (2005) [Pubmed]
  51. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. Guschin, D., Rogers, N., Briscoe, J., Witthuhn, B., Watling, D., Horn, F., Pellegrini, S., Yasukawa, K., Heinrich, P., Stark, G.R. EMBO J. (1995) [Pubmed]
  52. {beta}1 Integrin and IL-3R coordinately regulate STAT5 activation and anchorage-dependent proliferation. Defilippi, P., Rosso, A., Dentelli, P., Calvi, C., Garbarino, G., Tarone, G., Pegoraro, L., Brizzi, M.F. J. Cell Biol. (2005) [Pubmed]
  53. Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. Wakao, H., Harada, N., Kitamura, T., Mui, A.L., Miyajima, A. EMBO J. (1995) [Pubmed]
  54. A novel function for a glucose analog of blood group H antigen as a mediator of leukocyte-endothelial adhesion via intracellular adhesion molecule 1. Zhu, K., Amin, M.A., Kim, M.J., Katschke, K.J., Park, C.C., Koch, A.E. J. Biol. Chem. (2003) [Pubmed]
  55. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Bousquet, M., Quelen, C., De Mas, V., Duchayne, E., Roquefeuil, B., Delsol, G., Laurent, G., Dastugue, N., Brousset, P. Oncogene (2005) [Pubmed]
  56. Signaling pathways activated by the growth hormone receptor. Herrington, J., Carter-Su, C. Trends Endocrinol. Metab. (2001) [Pubmed]
  57. Constitutive nuclear localization of Janus kinases 1 and 2. Lobie, P.E., Ronsin, B., Silvennoinen, O., Haldosén, L.A., Norstedt, G., Morel, G. Endocrinology (1996) [Pubmed]
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