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Gene Review

Jak2  -  Janus kinase 2

Mus musculus

Synonyms: AI504024, C81284, JAK-2, Tyrosine-protein kinase JAK2
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Disease relevance of Jak2

  • Collectively, our data suggest that Jak2 is differentiation-inducing and growth-inhibitory in normal mammary epithelial cells, observations that may shed new light on the role of the Jak2-Stat5 pathway in breast cancer [1].
  • Janus kinase 2: a critical target in chronic myelogenous leukemia [2].
  • After in vivo administration of a high GH dose (5 microg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice [3].
  • BACKGROUND: A somatic activating mutation (V617F) in the JAK2 tyrosine kinase was recently discovered in the majority of patients with polycythemia vera (PV), and some with essential thrombocythemia (ET) and chronic idiopathic myelofibrosis [4].
  • JAK2 V617F also induced leukocytosis and neutrophilia that was much more prominent in Balb/c mice than in B6 [4].

High impact information on Jak2

  • The JAK2-GHR and JAK2-erythropoietin receptor interactions described here and in the accompanying paper provide a molecular basis for involvement of tyrosyl phosphorylation in physiological responses to these ligands and suggest a shared signaling mechanism among members of the cytokine/hematopoietin receptor family [5].
  • Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase [5].
  • Immunological approaches were used to establish GH-dependent complex formation between JAK2 and GHR, activation of JAK2 tyrosine kinase activity, and tyrosyl phosphorylation of both JAK2 and GHR [5].
  • When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2 [6].
  • Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis [7].

Chemical compound and disease context of Jak2


Biological context of Jak2


Anatomical context of Jak2


Associations of Jak2 with chemical compounds

  • This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR [16].
  • Jak2-deficient females were unable to lactate as a result of impaired alveologenesis [12].
  • Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells [2].
  • Coumermycin induced autophosphorylation of GyrB-Jak2 fusion proteins, thus bypassing receptor activation [17].
  • There was neither enhanced tyrosine phosphorylation of cellular protein content, Cbl, or Jak2, nor serine phosphorylation of MAP kinase or Akt [18].
  • Although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein [19].
  • We showed that a specific JAK2 inhibitor, AG490, potently inhibited cytokine-independent cell growth induced by JAK2 L611S mutant via the induction of apoptotic cell death [20].

Physical interactions of Jak2

  • PRL binding to its cognate receptor leads to receptor dimerization and activation of the tyrosine kinase Janus kinase 2 (JAK2), associated with the membrane-proximal, intracellular domain of the receptor [21].
  • Consistently, antibodies directed against the extracellular domain of OB-R coprecipitated Jak2 [22].
  • Electrophoretic mobility shift assays demonstrate that CD16/Jak2 activates the ability of signal transduction and activation of transcription (STAT) proteins to bind to an interferon-gamma-activated sequence oligonucleotide in a manner similar to that seen after IL-3 treatment [23].
  • Mutation of Tyr(441) also blocked the ability of SOCS-1 to bind to IFNGR1 and JAK2 in response to IFNgamma and the normal down-regulation of STAT1 activation and antiviral activity [24].
  • In accordance with this homology, we demonstrate that Jak-2 cofractionates and coimmunoprecipitates with caveolin-1 [25].

Enzymatic interactions of Jak2

  • In turn, JAK2 phosphorylates and activates STAT5, a member of the signal transducers and activators of transcription (STAT) family [21].
  • In contrast, immunoprecipitated JAK2 was not able to phosphorylate this same region of Cbl [26].
  • We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization [27].
  • Both the receptor and Janus kinase 2 were phosphorylated after erythropoietin stimulation of J2E-NR cells [28].
  • Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum [29].

Regulatory relationships of Jak2

  • Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation [30].
  • Stat 1 and 3 were also activated presumably downstream to JAK2 activation [31].
  • Through the expression of EPOR carboxyl-terminal truncation mutants in FDC-P1 cells, we presently show that an EPOR form truncated within the ExBx2 domain efficiently activates Jak2, yet is deficient in mitogenesis [32].
  • The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL-induced, but not PGE1-induced, Cl- transport [33].
  • Pyk2 is selectively associated with Jak2 and activated by IFN-gamma [34].

Other interactions of Jak2

  • Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways [35].
  • To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2 [36].
  • Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat) [12].
  • Here we report a novel signaling pathway of EphA4, which involves activation of the tyrosine kinase Jak2 and the transcriptional activator Stat3 [14].
  • Surprisingly, we also found that Jak2, a proto-oncogene located between Cd95 and Pten, was simultaneously inactivated in a significant fraction of the tumors analysed (24 of 34, 70.6%) [37].

Analytical, diagnostic and therapeutic context of Jak2


  1. Role of tyrosine kinase Jak2 in prolactin-induced differentiation and growth of mammary epithelial cells. Xie, J., LeBaron, M.J., Nevalainen, M.T., Rui, H. J. Biol. Chem. (2002) [Pubmed]
  2. Janus kinase 2: a critical target in chronic myelogenous leukemia. Samanta, A.K., Lin, H., Sun, T., Kantarjian, H., Arlinghaus, R.B. Cancer Res. (2006) [Pubmed]
  3. Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance. Miquet, J.G., Sotelo, A.I., Dominici, F.P., Bonkowski, M.S., Bartke, A., Turyn, D. J. Endocrinol. (2005) [Pubmed]
  4. Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F. Zaleskas, V.M., Krause, D.S., Lazarides, K., Patel, N., Hu, Y., Li, S., Van Etten, R.A. PLoS ONE (2006) [Pubmed]
  5. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Argetsinger, L.S., Campbell, G.S., Yang, X., Witthuhn, B.A., Silvennoinen, O., Ihle, J.N., Carter-Su, C. Cell (1993) [Pubmed]
  6. Structure and function of a new STAT-induced STAT inhibitor. Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., Akira, S., Kishimoto, T. Nature (1997) [Pubmed]
  7. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., Leeder, J.S., Freedman, M., Cohen, A., Gazit, A., Levitzki, A., Roifman, C.M. Nature (1996) [Pubmed]
  8. Poxvirus infection rapidly activates tyrosine kinase signal transduction. Masters, J., Hinek, A.A., Uddin, S., Platanias, L.C., Zeng, W., McFadden, G., Fish, E.N. J. Biol. Chem. (2001) [Pubmed]
  9. A transient dephosphorylation of JAK1 and JAK2 characterises the early-phase response of murine erythroleukemia cells to the differentiation inducer hexamethylenebisacetamide. Arcangeli, A., Fontana, L., Crociani, O., Cherubini, A., Hofmann, G., Piccini, E., Polvani, S., D'Amico, M., Carlà, M., Olivotto, M. Leukemia (2000) [Pubmed]
  10. Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. Choi, J.H., Kim, H.S., Kim, S.H., Yang, Y.R., Bae, Y.S., Chang, J.S., Moo Kwon, H., Ryu, S.H., Suh, P.G. Nat. Cell Biol. (2006) [Pubmed]
  11. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Silvennoinen, O., Witthuhn, B.A., Quelle, F.W., Cleveland, J.L., Yi, T., Ihle, J.N. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  12. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Wagner, K.U., Krempler, A., Triplett, A.A., Qi, Y., George, N.M., Zhu, J., Rui, H. Mol. Cell. Biol. (2004) [Pubmed]
  13. Erythropoietin-dependent inhibition of apoptosis is supported by carboxyl-truncated receptor forms and blocked by dominant-negative forms of Jak2. Zhuang, H., Niu, Z., He, T.C., Patel, S.V., Wojchowski, D.M. J. Biol. Chem. (1995) [Pubmed]
  14. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. Lai, K.O., Chen, Y., Po, H.M., Lok, K.C., Gong, K., Ip, N.Y. J. Biol. Chem. (2004) [Pubmed]
  15. Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Krempler, A., Qi, Y., Triplett, A.A., Zhu, J., Rui, H., Wagner, K.U. Genesis (2004) [Pubmed]
  16. Friend spleen focus-forming virus transforms rodent fibroblasts in cooperation with a short form of the receptor tyrosine kinase Stk. Nishigaki, K., Hanson, C., Jelacic, T., Thompson, D., Ruscetti, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. Activation and functional analysis of Janus kinase 2 in BA/F3 cells using the coumermycin/gyrase B system. Mohi, M.G., Arai, K., Watanabe, S. Mol. Biol. Cell (1998) [Pubmed]
  18. Suppression of apoptosis and granulocyte colony-stimulating factor-induced differentiation by an oncogenic form of Cbl. Sinha, S., Jancarik, J., Roginskaya, V., Rothermund, K., Boxer, L.M., Corey, S.J. Exp. Hematol. (2001) [Pubmed]
  19. The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Hookham, M.B., Elliott, J., Suessmuth, Y., Staerk, J., Ward, A.C., Vainchenker, W., Percy, M.J., McMullin, M.F., Constantinescu, S.N., Johnston, J.A. Blood (2007) [Pubmed]
  20. The acute lymphoblastic leukemia-associated JAK2 L611S mutant induces tumorigenesis in nude mice. Funakoshi-Tago, M., Tago, K., Sumi, K., Abe, M., Aizu-Yokota, E., Oshio, T., Sonoda, Y., Kasahara, T. J. Biol. Chem. (2009) [Pubmed]
  21. A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. Aoki, N., Matsuda, T. J. Biol. Chem. (2000) [Pubmed]
  22. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Ghilardi, N., Skoda, R.C. Mol. Endocrinol. (1997) [Pubmed]
  23. Signal transduction by a CD16/CD7/Jak2 fusion protein. Sakai, I., Nabell, L., Kraft, A.S. J. Biol. Chem. (1995) [Pubmed]
  24. Role of tyrosine 441 of interferon-gamma receptor subunit 1 in SOCS-1-mediated attenuation of STAT1 activation. Qing, Y., Costa-Pereira, A.P., Watling, D., Stark, G.R. J. Biol. Chem. (2005) [Pubmed]
  25. Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. Park, D.S., Lee, H., Frank, P.G., Razani, B., Nguyen, A.V., Parlow, A.F., Russell, R.G., Hulit, J., Pestell, R.G., Lisanti, M.P. Mol. Biol. Cell (2002) [Pubmed]
  26. Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase. Hunter, S., Burton, E.A., Wu, S.C., Anderson, S.M. J. Biol. Chem. (1999) [Pubmed]
  27. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Narazaki, M., Witthuhn, B.A., Yoshida, K., Silvennoinen, O., Yasukawa, K., Ihle, J.N., Kishimoto, T., Taga, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  28. Disrupted signaling in a mutant J2E cell line that shows enhanced viability, but does not proliferate or differentiate, with erythropoietin. Tilbrook, P.A., Bittorf, T., Busfield, S.J., Chappell, D., Klinken, S.P. J. Biol. Chem. (1996) [Pubmed]
  29. Growth hormone-dependent tyrosine phosphorylation of a GH receptor-associated high molecular WEIGHT protein immunologically related to JAK2. Jiang, J., Liang, L., Kim, S.O., Zhang, Y., Mandler, R., Frank, S.J. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  30. The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. Monni, R., Santos, S.C., Mauchauffe, M., Berger, R., Ghysdael, J., Gouilleux, F., Gisselbrecht, S., Bernard, O., Penard-Lacronique, V. Oncogene (2001) [Pubmed]
  31. Prolactin concurrently activates src-PLD and JAK/Stat signaling pathways to induce proliferation while promoting differentiation in embryonic astrocytes. Mangoura, D., Pelletiere, C., Leung, S., Sakellaridis, N., Wang, D.X. Int. J. Dev. Neurosci. (2000) [Pubmed]
  32. The extended box 2 subdomain of erythropoietin receptor is nonessential for Jak2 activation yet critical for efficient mitogenesis in FDC-ER cells. He, T.C., Jiang, N., Zhuang, H., Quelle, D.E., Wojchowski, D.M. J. Biol. Chem. (1994) [Pubmed]
  33. Janus kinase 2 (JAK2) regulates prolactin-mediated chloride transport in mouse mammary epithelial cells through tyrosine phosphorylation of Na+-K+-2Cl- cotransporter. Selvaraj, N.G., Omi, E., Gibori, G., Rao, M.C. Mol. Endocrinol. (2000) [Pubmed]
  34. Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-gamma, but not IFN-alpha, signaling. Takaoka, A., Tanaka, N., Mitani, Y., Miyazaki, T., Fujii, H., Sato, M., Kovarik, P., Decker, T., Schlessinger, J., Taniguchi, T. EMBO J. (1999) [Pubmed]
  35. Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Tong, W., Zhang, J., Lodish, H.F. Blood (2005) [Pubmed]
  36. Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Ho, J.M., Beattie, B.K., Squire, J.A., Frank, D.A., Barber, D.L. Blood (1999) [Pubmed]
  37. Evidence of a possible epigenetic inactivation mechanism operating on a region of mouse chromosome 19 in gamma-radiation-induced thymic lymphomas. Santos, J., Herranz, M., Fernández, M., Vaquero, C., López, P., Fernández-Piqueras, J. Oncogene (2001) [Pubmed]
  38. The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl. Drachman, J.G., Griffin, J.D., Kaushansky, K. J. Biol. Chem. (1995) [Pubmed]
  39. In vivo selection of genetically modified erythroid cells using a jak2-based cell growth switch. Zhao, S., Weinreich, M.A., Ihara, K., Richard, R.E., Blau, C.A. Mol. Ther. (2004) [Pubmed]
  40. Localization of janus kinase 2 to the nuclei of mature oocytes and early cleavage stage mouse embryos. Ito, M., Nakasato, M., Suzuki, T., Sakai, S., Nagata, M., Aoki, F. Biol. Reprod. (2004) [Pubmed]
  41. Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy. Beckles, D.L., Mascareno, E., Siddiqui, M.A. Vascul. Pharmacol. (2006) [Pubmed]
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