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Gene Review

JAK1  -  Janus kinase 1

Homo sapiens

Synonyms: JAK-1, JAK1A, JAK1B, JTK3, Tyrosine-protein kinase JAK1
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Disease relevance of JAK1


High impact information on JAK1

  • Here we discuss one of the early signaling pathways activated by chemokines, the JAK/STAT pathway [7].
  • JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival [8].
  • JAK signaling globally counteracts heterochromatic gene silencing [8].
  • Thus, a localized signal activates the JAK/STAT pathway in neighboring epithelial cells, causing them to become invasive [9].
  • Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila [9].

Chemical compound and disease context of JAK1


Biological context of JAK1


Anatomical context of JAK1


Associations of JAK1 with chemical compounds


Physical interactions of JAK1

  • We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase [26].
  • Direct activation of the Jak/Stat system via the uPA-receptor complex may be an important mechanism for endothelial cell migration and/or proliferation during angiogenesis and after vascular injury [27].
  • METHODS/RESULTS: IFN binding to its specific cell surface receptor leads to activation of the Janus family tyrosine kinase (JAK) - signal transducer and activator of transcription (STAT) pathway [28].
  • Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2 [29].
  • In contrast, the KIR of CIS3 showed stronger potential for both binding to JH1 and inhibition of JAK kinase activity than that of JAB [30].

Enzymatic interactions of JAK1

  • Jak1 may therefore be the enzyme that phosphorylates Tyr 701 in Stat91 [31].
  • The growth rates negatively correlated with levels of both IRF-1 expression and constitutively phosphorylated Jak1 [32].
  • JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied [33].
  • These negative regulatory effects on Ig class switching were concomitant with the ability of CD45 to dephosphorylate the induced phosphorylation of JAK1, JAK3, and signal transducer and activator of transcription 6, but not on stress-activated/mitogen-activated protein kinases [34].
  • However, we were unable to show that JAK1 is tyrosine phosphorylated and activated by IL-11 under identical conditions [35].

Co-localisations of JAK1


Regulatory relationships of JAK1

  • The kinetic studies indicate that tyrosine phosphorylation and activation of JAK kinases induced by IL-9 occurred within 1 minute, peaked by 5 to 10 minutes, and persisted at least for 45 minutes [37].
  • Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation [38].
  • Further, decidual PRL through a paracrine mechanism may influence glandular epithelial function/secretions and direct gene transcription through the JAK/STAT pathway [39].
  • Furthermore, while investigating the IL-6 signaling pathway leading to Mcl-1 up-regulation, we show that a janus kinase (JAK)-2 inhibitor is able to inhibit both STAT3 activation and Mcl-1 up-regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect [40].
  • The JAK inhibitor AG-490 blocked cytokine-induced STAT 5 phosphorylation and proliferation of M-07e cells in a dose-dependent manner [41].

Other interactions of JAK1


Analytical, diagnostic and therapeutic context of JAK1


  1. Interferon alpha activates NF-kappaB in JAK1-deficient cells through a TYK2-dependent pathway. Yang, C.H., Murti, A., Valentine, W.J., Du, Z., Pfeffer, L.M. J. Biol. Chem. (2005) [Pubmed]
  2. JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. Staerk, J., Kallin, A., Demoulin, J.B., Vainchenker, W., Constantinescu, S.N. J. Biol. Chem. (2005) [Pubmed]
  3. Tyrosine phosphorylation and activation of Janus kinase 1 and STAT3 by sublytic C5b-9 complement complex in aortic endothelial cells. Niculescu, F., Soane, L., Badea, T., Shin, M., Rus, H. Immunopharmacology (1999) [Pubmed]
  4. KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. Osborne, J., Moore, P.S., Chang, Y. Hum. Immunol. (1999) [Pubmed]
  5. Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis. Rossi, M.R., Hawthorn, L., Platt, J., Burkhardt, T., Cowell, J.K., Ionov, Y. Cancer Genet. Cytogenet. (2005) [Pubmed]
  6. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Jeong, E.G., Kim, M.S., Nam, H.K., Min, C.K., Lee, S., Chung, Y.J., Yoo, N.J., Lee, S.H. Clin. Cancer Res. (2008) [Pubmed]
  7. Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Mellado, M., Rodríguez-Frade, J.M., Mañes, S., Martínez-A, C. Annu. Rev. Immunol. (2001) [Pubmed]
  8. JAK signaling globally counteracts heterochromatic gene silencing. Shi, S., Calhoun, H.C., Xia, F., Li, J., Le, L., Li, W.X. Nat. Genet. (2006) [Pubmed]
  9. Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Silver, D.L., Montell, D.J. Cell (2001) [Pubmed]
  10. 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]
  11. Regulation of macrophage activation. Ma, J., Chen, T., Mandelin, J., Ceponis, A., Miller, N.E., Hukkanen, M., Ma, G.F., Konttinen, Y.T. Cell. Mol. Life Sci. (2003) [Pubmed]
  12. Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress. Monroe, R.K., Halvorsen, S.W. Free Radic. Biol. Med. (2006) [Pubmed]
  13. Silymarin protects pancreatic beta-cells against cytokine-mediated toxicity: implication of c-Jun NH2-terminal kinase and janus kinase/signal transducer and activator of transcription pathways. Matsuda, T., Ferreri, K., Todorov, I., Kuroda, Y., Smith, C.V., Kandeel, F., Mullen, Y. Endocrinology (2005) [Pubmed]
  14. 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]
  15. Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors. Chen, H., Lee, J.M., Zong, Y., Borowitz, M., Ng, M.H., Ambinder, R.F., Hayward, S.D. J. Virol. (2001) [Pubmed]
  16. Altered p-JAK1 expression is associated with estrogen receptor status in breast infiltrating ductal carcinoma. Yeh, Y.T., Ou-Yang, F., Chen, I.F., Yang, S.F., Su, J.H., Hou, M.F., Yuan, S.S. Oncol. Rep. (2007) [Pubmed]
  17. Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-beta1 is mediated by caspase-dependent and -independent processes. Wierenga, A.T., Schuringa, J.J., Eggen, B.J., Kruijer, W., Vellenga, E. Leukemia (2002) [Pubmed]
  18. The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Kruse, S., Japha, T., Tedner, M., Sparholt, S.H., Forster, J., Kuehr, J., Deichmann, K.A. Immunology (1999) [Pubmed]
  19. Involvement of Stat3 in interleukin-6-induced IgM production in a human B-cell line. Faris, M., Kokot, N., Stahl, N., Nel, A.E. Immunology (1997) [Pubmed]
  20. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. Beadling, C., Guschin, D., Witthuhn, B.A., Ziemiecki, A., Ihle, J.N., Kerr, I.M., Cantrell, D.A. EMBO J. (1994) [Pubmed]
  21. Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. Haque, S.J., Wu, Q., Kammer, W., Friedrich, K., Smith, J.M., Kerr, I.M., Stark, G.R., Williams, B.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  22. JAK1-dependent phosphorylation of insulin receptor substrate-1 (IRS-1) is inhibited by IRS-1 serine phosphorylation. Cengel, K.A., Freund, G.G. J. Biol. Chem. (1999) [Pubmed]
  23. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. Miller, D.M., Rahill, B.M., Boss, J.M., Lairmore, M.D., Durbin, J.E., Waldman, J.W., Sedmak, D.D. J. Exp. Med. (1998) [Pubmed]
  24. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Calvisi, D.F., Ladu, S., Gorden, A., Farina, M., Conner, E.A., Lee, J.S., Factor, V.M., Thorgeirsson, S.S. Gastroenterology (2006) [Pubmed]
  25. 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells. Rajasingh, J., Bright, J.J. Exp. Cell Res. (2006) [Pubmed]
  26. Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. Kirken, R.A., Rui, H., Malabarba, M.G., Farrar, W.L. J. Biol. Chem. (1994) [Pubmed]
  27. Urokinase activates the Jak/Stat signal transduction pathway in human vascular endothelial cells. Dumler, I., Kopmann, A., Weis, A., Mayboroda, O.A., Wagner, K., Gulba, D.C., Haller, H. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
  28. Interferon-induced gene expression and signaling in human hepatoma cell lines. Melén, K., Keskinen, P., Lehtonen, A., Julkunen, I. J. Hepatol. (2000) [Pubmed]
  29. Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. Gao, B., Shen, X., Kunos, G., Meng, Q., Goldberg, I.D., Rosen, E.M., Fan, S. FEBS Lett. (2001) [Pubmed]
  30. 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]
  31. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Shuai, K., Ziemiecki, A., Wilks, A.F., Harpur, A.G., Sadowski, H.B., Gilman, M.Z., Darnell, J.E. Nature (1993) [Pubmed]
  32. Growth arrest of epithelial cells during measles virus infection is caused by upregulation of interferon regulatory factor 1. Yokota, S., Okabayashi, T., Yokosawa, N., Fujii, N. J. Virol. (2004) [Pubmed]
  33. Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Murata, T., Husain, S.R., Mohri, H., Puri, R.K. Int. Immunol. (1998) [Pubmed]
  34. CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase. Yamada, T., Zhu, D., Saxon, A., Zhang, K. J. Biol. Chem. (2002) [Pubmed]
  35. Identification of a 130-kilodalton tyrosine-phosphorylated protein induced by interleukin-11 as JAK2 tyrosine kinase, which associates with gp130 signal transducer. Yin, T., Yasukawa, K., Taga, T., Kishimoto, T., Yang, Y.C. Exp. Hematol. (1994) [Pubmed]
  36. Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells. Yan, C., Naltner, A., Martin, M., Naltner, M., Fangman, J.M., Gurel, O. J. Biol. Chem. (2002) [Pubmed]
  37. Tyrosine phosphorylation and activation of JAK family tyrosine kinases by interleukin-9 in MO7E cells. Yin, T., Yang, L., Yang, Y.C. Blood (1995) [Pubmed]
  38. JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. Legendre, F., Dudhia, J., Pujol, J.P., Bogdanowicz, P. J. Biol. Chem. (2003) [Pubmed]
  39. Expression of functional prolactin receptors in nonpregnant human endometrium: janus kinase-2, signal transducer and activator of transcription-1 (STAT1), and STAT5 proteins are phosphorylated after stimulation with prolactin. Jabbour, H.N., Critchley, H.O., Boddy, S.C. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  40. IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras / MAP kinase pathway. Puthier, D., Bataille, R., Amiot, M. Eur. J. Immunol. (1999) [Pubmed]
  41. Effects of thrombopoietin, interleukin-3 and the kinase inhibitor K-252a on growth and polyploidization of the megakaryocytic cell line M-07e. Quentmeier, H., Zaborski, M., Drexler, H.G. Leukemia (1998) [Pubmed]
  42. 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]
  43. 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]
  44. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. He, B., You, L., Uematsu, K., Zang, K., Xu, Z., Lee, A.Y., Costello, J.F., McCormick, F., Jablons, D.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  45. A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Kohlhuber, F., Rogers, N.C., Watling, D., Feng, J., Guschin, D., Briscoe, J., Witthuhn, B.A., Kotenko, S.V., Pestka, S., Stark, G.R., Ihle, J.N., Kerr, I.M. Mol. Cell. Biol. (1997) [Pubmed]
  46. Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli. Hosui, A., Ohkawa, K., Ishida, H., Sato, A., Nakanishi, F., Ueda, K., Takehara, T., Kasahara, A., Sasaki, Y., Hori, M., Hayashi, N. J. Biol. Chem. (2003) [Pubmed]
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