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Jak2 tyrosine kinase

A mediator of both housekeeping and ligand-dependent gene expression?

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Abstract

Jak2 is a nonreceptor tyrosine kinase that is essential for proper animal development and physiology. It is activated by ligand-occupied cell-surface receptors. Once activated, it then tyrosine phosphorylates the latent cytoplasmic transcription factors, termed the signal transducers and activators of transcription (STAT) proteins. Thus Jak2 is viewed as a classic mediator of ligand-dependent signal transduction. Recent studies, however, suggest that Jak2 may mediate cellular gene expression outside of the classically defined, ligand-activated, Jak/STAT-signaling paradigm. Here we review these studies, provide additional data, and discuss whether Jak2 is a mediator of ligand-independent gene transcription, and, in turn, whether our current understanding of the Jak/STAT signaling paradigm should be modified to incorporate these observations.

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References

  1. Frank, S. J., Gilliland, G., Kraft, A. S., and Arnold, C. S. (1994) Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase. Endocrinology 135, 2228–2239.

    Article  PubMed  CAS  Google Scholar 

  2. Ali, M. S., Sayeski, P. P., Dirksen, L. B., Hayzer, D. J., Marrero, M. B., and Bernstein, K. E. (1997) Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor. J. Biol. Chem. 272, 23382–23388.

    Article  PubMed  CAS  Google Scholar 

  3. Sayeski, P. P., Ali, M. S., Frank, S. J., and Bernstein K. E. (2001) The angiotensin II-dependent nuclear translocation of Stat1 is mediated by the Jak2 protein motif 231YRFRR. J. Biol. Chem. 276, 10556–10563.

    Article  PubMed  CAS  Google Scholar 

  4. Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Yi, T., Tang, B., Miura, O., and Ihle J. N. (1993) JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythro-poietin. Cell 74, 227–236.

    Article  PubMed  CAS  Google Scholar 

  5. Argetsinger, L. S., Campbell, G. S., Yang, X., Witthuhn, B. A., Silvennoinen, O., Ihle, J. N., et al. (1993) Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74, 237–244.

    Article  PubMed  CAS  Google Scholar 

  6. Rui, H., Kirken, R. A., and Farrar, W. L. (1994) Activation of receptor-associated tyrosine kinase JAK2 by prolactin. J. Biol. Chem. 269, 5364–5368.

    PubMed  CAS  Google Scholar 

  7. Narazaki, M., Witthuhn, B. A., Yoshida, K., Silvennoinen, O., Yasukawa, K., Ihle, J. N., et al. (1994) Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc. Natl. Acad. Sci. U S A 91, 2285–2289.

    Article  PubMed  CAS  Google Scholar 

  8. Marrero, M. B., Schieffer, B., Paxton, W. G., Heerdt, L., Berk, B. C., Delafontaine, P., et al. (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375, 247–250.

    Article  PubMed  CAS  Google Scholar 

  9. Saharinen, P., Takaluoma, K., and Silvennoinen, O. (2000) Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol. 20, 3387–3395.

    Article  PubMed  CAS  Google Scholar 

  10. Saharinen, P. and Silvennoinen, O. (2002) The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J. Biol. Chem. 277, 47954–47963.

    Article  PubMed  CAS  Google Scholar 

  11. Bernards, A. (1991) Predicted Tyk2 protein contains two tandem protein kinase domains. Oncogene 6, 1185–1187.

    PubMed  CAS  Google Scholar 

  12. Harpur, A. G., Andres, A. C., Ziemiecki, A., Aston, R. R., and Wilks, A. F. (1992) JAK2, a third member of the JAK family of protein tyrosine kinases. Oncogene 7, 1347–1353.

    PubMed  CAS  Google Scholar 

  13. Higgins, D. G., Thompson, J. D., and Gibson, T. J. (1996) Using CLUSTAL for multiple sequence alignments. Meth. Enzymol. 266, 383–402.

    Article  PubMed  CAS  Google Scholar 

  14. Kampa, D. and Burnside, J. (2000) Computational and functional analysis of the putative SH2 domain in Janus kinases. Biochem. Biophys. Res. Comm. 278, 175–182.

    Article  PubMed  CAS  Google Scholar 

  15. Giordanetto, F., and Kroemer, R. T. (2002) Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7. Protein Engineering 15, 727–737.

    Article  PubMed  CAS  Google Scholar 

  16. Girault, J. A., Labesse, G., Mornon, J., and Callebaut, I. (1998) Janus kinases and focal adhesion kinases play in the 4.1 band: a superfamily of band 4.1 domains important for cell structure and signal transduction. Mol. Med. 4, 751–769.

    PubMed  CAS  Google Scholar 

  17. Yonemura, S., Hirao, M., Doi, Y., Takahashi, N., Kondo, T., Tsukita, S., et al. (1998) Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J. Cell. Biol. 140, 885–895.

    Article  PubMed  CAS  Google Scholar 

  18. Tanner, J. W., Chen, W., Young, R. L., Longmore, G. D., and Shaw, A. S. (1995) The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. J. Biol. Chem. 270, 6523–6530.

    Article  PubMed  CAS  Google Scholar 

  19. Zhao, Y. M., Wagner, F., Frank, S. J., and Kraft, A. S. (1995) The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte macrophage colony-stimulating factor receptor beta c chain. J. Biol. Chem. 270, 13814–13818.

    Article  PubMed  CAS  Google Scholar 

  20. Schindler, C., Shuai, K., Prezioso, V. R., and Darnell, J. E., Jr. (1992) Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257, 809–813.

    Article  PubMed  CAS  Google Scholar 

  21. Ju, H., Venema, V. J., Liang, H., Harris, M. B., Zou, R., and Venema, R. C. (2000) Bradykinin activates the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway in vascular endothelial cells: localization of JAK/STAT signaling proteins in plasmalemmal caveolae. Biochem. J. 351, 257–264.

    Article  PubMed  CAS  Google Scholar 

  22. Peeler, T. C., Conrad, K. M., and Baker, K. M. (1996) Endothelin stimulates sis-inducing factor-like DNA binding activity in CHO-K1 cells expressing ETa receptors. Biochem. Biophys. Res. Comm. 221, 62–66.

    Article  PubMed  CAS  Google Scholar 

  23. Lukashova, V., Chen, Z., Duhe, R. J., Rola-Pleszczynski, M., and Stankova, J. (2003) Janus kinase 2 activation by the platelet-activating factor receptor (PAFR): roles of Tyk2 and PAFR C terminus. J. Immunol. 171, 3794–3800.

    PubMed  CAS  Google Scholar 

  24. Buggy, J. J. (1998) Binding of α-melanocyte-stimulating hormone to its G protein-coupled receptor on B-lymphocytes activates the Jak/Stat pathway. Biochem. J. 331, 211–216.

    PubMed  CAS  Google Scholar 

  25. Sasaguri, T., Teruya, H., Ishida, A., Abumiya, T., and Ogata, J. (2000) Linkage between α1 adrenergic receptor and the Jak/Stat signaling pathway in vascular smooth muscle cells. Biochem. Biophys. Res. Comm. 268, 25–30.

    Article  PubMed  CAS  Google Scholar 

  26. Meuller, A. and Strange, P. G. (2004) CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (Jak2) and Gi proteins. FEBS Lett. 570, 126–132.

    Article  CAS  Google Scholar 

  27. Huang, L. J., Constantinescu, S. N., and Lodish, H. F. (2001) The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol. Cell 8, 1327–1338.

    Article  PubMed  CAS  Google Scholar 

  28. Harrison, D. A., Binari, R., Nahreini, T. S., Gilman, M., and Perrimon, N. (1995) Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J. 14, 2857–2865.

    PubMed  CAS  Google Scholar 

  29. Luo, H., Rose, P., Barber, D., Hanratty, W. P., Lee, S., Roberts, T. M. et al. (1997) Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol. Cell. Biol. 17, 1562–1571.

    PubMed  CAS  Google Scholar 

  30. Lacronique, V., Boureux, A., Valle, V. D., Poirel, H., Quang, C. T., Mauchauffe, M., et al. (1997) A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278, 1309–1312.

    Article  PubMed  CAS  Google Scholar 

  31. Peeters, P., Raynaud, S. D., Cools, J., Wlodarska, I., Grosgeorge, J., Philip, P., et al. (1997) 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. Blood 90, 2535–2540.

    PubMed  CAS  Google Scholar 

  32. Ho, J. M., Beattie, B. K., Squire, J. A., Frank, D. A., and Barber, D. L. (1999) Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Blood 93, 4354–4364.

    PubMed  CAS  Google Scholar 

  33. Lacronique, V., Boureux, A., Monni, R., Dumon, S., Mauchauffe, M., Mayeux, P., et al. (2000) Transforming properties of chimeric TEL-JAK proteins in BA/F3 cells. Blood 95, 2076–2083.

    PubMed  CAS  Google Scholar 

  34. Carron, C., Cormier, F., Janin, A., Lacronique, V., Giovannini, M., Daniel, M. T., et al. (2000) TEL-JAK2 transgenic mice develop T-cell leukemia. Blood 95, 3891–3899.

    PubMed  CAS  Google Scholar 

  35. Feng, J., Witthuhn, B. A., Matsuda, T., Kohlhuber, F., Kerr, I. M., and Ihle, J. N. (1997) Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell. Biol. 17, 2497–2501.

    PubMed  CAS  Google Scholar 

  36. Feener, E. P., Rosario, F., Dunn, S. L., Stancheva, Z., and Myers, M. G. Jr. (2004) Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling. Mol. Cell. Biol. 11, 4968–4978.

    Article  CAS  Google Scholar 

  37. Argetsinger, L. S., Kouadio, J. L., Steen, H., Stensballe, A., Jensen, O. N., and Carter-Su, C. (2004) Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol. Cell. Biol. 11, 4955–4967.

    Article  CAS  Google Scholar 

  38. Kurzer, J. H., Argetsinger, L. S., Zhou, Y. J., Kouadio, J. L., O'Shea, J. J., and Carter-Su, C. (2004) Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol. Cell. Biol. 10, 4557–4570.

    Article  CAS  Google Scholar 

  39. Rui, L., Mathews, L. S., Hotta, K., Gustafson, T. A., and Carter-Su, C. (1997) Identification of SH2-Bb as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Mol. Cell. Biol. 17, 6633–6644.

    PubMed  CAS  Google Scholar 

  40. Yin, T., Shen, R., Feng, G. S., and Yang, Y. C. (1997) Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases. J. Biol. Chem. 272, 1032–1037.

    Article  PubMed  CAS  Google Scholar 

  41. Chatti, K., Farrar, W. L., and Duhe, R. J. (2004) Tyrosine phosphorylation of the Janus kinase 2 activation loop is essential for a high-activity catalytic state but dispensable for a basal catalytic state. Biochemistry 43, 4272–4283.

    Article  PubMed  CAS  Google Scholar 

  42. Wallace, T. W., VonDerLinden, D., He, K., Frank, S. J., and Sayeski, P. P. (2004) Microarray analyses identify JAK2 tyrosine kinase as a key mediator of ligand-independent gene expression. Am. J. Physiol. Cell Physiol. 287, C981-C991.

    Article  PubMed  CAS  Google Scholar 

  43. Kohlhuber, F., Rogers, N. C., Watling, D., Feng, J., Guschin, D., Briscoe, J., et al. (1997) A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses. Mol. Cell. Biol. 17, 695–706.

    PubMed  CAS  Google Scholar 

  44. Sayeski, P. P., Ali, M. S., Safavi, A., Lyles, M., Kim, S. O., Frank, S. J., et al. (1999) A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn. J. Biol. Chem. 274, 33131–33142.

    Article  PubMed  CAS  Google Scholar 

  45. Hafner, C., Schmitz, G., Meyer, S., Bataille, F., Hau, P., Langmann, T., et al. (2004) Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin. Chem. 50, 490–499.

    Article  PubMed  CAS  Google Scholar 

  46. Tang, X. X., Evans, A. E., Zhao, H., Cnaan, A., London, W., Cohn, S. L., et al. (1999) High-level expression of EphB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas. Clin. Cancer Res. 35, 1491–1496.

    Google Scholar 

  47. Fox, B. P. and Kandpal, R. P. (2004) Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem. Biophys. Res. Commun. 318, 882–892.

    Article  PubMed  CAS  Google Scholar 

  48. He, K., Wang, X., Jiang, J., Guan, R., Bernstein, K. E., Sayeski, P. P., et al. (2003) JAK2 determinants for GH receptor association, surface assembly, and signaling. Mol. Endocrinol. 17, 2211–2227.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL

    Tiffany A. Wallace & Peter P. Sayeski

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  1. Tiffany A. Wallace
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  2. Peter P. Sayeski
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Correspondence to Peter P. Sayeski.

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Wallace, T.A., Sayeski, P.P. Jak2 tyrosine kinase. Cell Biochem Biophys 44, 213–222 (2006). https://doi.org/10.1385/CBB:44:2:213

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