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Jak2 tyrosine kinase

A true jak of all trades?

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Abstract

Discovered roughly 10 yr ago, Jak2 tyrosine kinase has emerged as a critical molecule in mammalian development, physiology, and disease. Here, we review the early history of Jak2 and its role in health and disease. We will also review, its critical role in mediating cytokine-dependent signal transduction. Additionally, more recent work demonstrating the importance of Jak2 in G protein-coupled receptor and tyrosine kinase growth factor receptor signal transduction will be discussed. The cellular and biochemical mechanisms by which Jak2 tyrosine kinase is activated and regulated within the cell also will be reviewed. Finally, structure-function and pharmacological-based studies that identified structural motifs and amino acids within Jak2 that are critical for its function will be examined. By reviewing the biology of Jak2 tyrosine kinase at the molecular. cellular, and physiological levels, we hope to advance the understanding of how a single gene can have such a profound impact on development, physiology, and disease.

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References

  1. Firmbach-Kraft, I., Byers, M., Shows, T., Dalla-Favera, R., and Krobewski, J. J. (1990) Tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 5, 1329–1336.

    PubMed  CAS  Google Scholar 

  2. Wilks, A. F., Harpur, A. G., Kurban, R. R., Ralph, S. J., Zurcher, G., and Ziemiecki, A. (1991) Two novel protein-tyrosine kinases, each with a second phosphotransferaserelated catalytic domain, define a new class of protein kinase. Mol. Cell Biol. 11, 2057–2065.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  4. Duhe, R. J., Rui, H., Greenwood J. D., Garvey, K., and Farrar, W. L. (1995) Coloning of the gene encoding rat JAK2, a protein tyrosine kinase. Gene 158, 281–285.

    PubMed  CAS  Google Scholar 

  5. Kawamura, M., McVicar, D. W., Johnston, J. A., Blake, T. B., Chen, Y. Q., Lal, B. K., et al. (1994) Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc. Natl. Acad. Sci. U. S. A. 91, 6374–6378.

    PubMed  CAS  Google Scholar 

  6. Takahashi, T. and Shirasawa, T. (1994) Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases. FEBS Lett. 342, 124–128.

    PubMed  CAS  Google Scholar 

  7. Rane, S. G. and Reddy, E. P. (1994) JAK3 a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Oncogene 9, 2415–2423.

    PubMed  CAS  Google Scholar 

  8. Oates, A. C., Brownlie, A., Pratt, S. J., Irvine, D. V., Liao, E. C., Paw, B. H., et al. (1999) Gene duplication of zebrafish JAK2 homologs is accompanied by divergent embryonic expression patterns: only jak2a is expressed during erythropoiesis. Blood 94, 2622–2636.

    PubMed  CAS  Google Scholar 

  9. Binari, R., Perrimon, N. (1994) Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. Genes Dev. 8, 300–312.

    PubMed  CAS  Google Scholar 

  10. Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Yi, T., Tang, B., Miura, O., et al. (1993) JAK2 associates with the erythropietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74, 227–236.

    PubMed  CAS  Google Scholar 

  11. 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.

    PubMed  CAS  Google Scholar 

  12. Silvennoinen, O., Witthuhn, B. A., Quelle, F. W., Cleveland, J. L., Yi, T., and Ihle, J. N. (1993) Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc. Natl. Acad. Sci. U. S. A. 90, 8429–8433.

    PubMed  CAS  Google Scholar 

  13. Rui, H., Kirlen, 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 

  14. 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.

    PubMed  CAS  Google Scholar 

  15. Watling, D., Guschin, D., Muller, M., Silvennoinen, O., Witthuln, B. A., Quelle, F. W., et al. (1993) Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature 366, 166–170.

    PubMed  CAS  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. Shuai, K., Schindler, C., Prezioso, V. R., and Darnell, J. E., Jr. (1992) Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science 258, 1808–1812.

    PubMed  CAS  Google Scholar 

  18. Gadina, M., Hilton, D., Johnston, J. A., Morinobu, A., Lighvani, A., Zhou, Y. J., et al. (2001) Signaling by type I and II cytokine receptors: ten years after. Curr: Opin Immunol. 13, 363–373.

    CAS  Google Scholar 

  19. Kisseleva, T., Bhattacharya, S., Braunstein, J., and Schindler, C. W. (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24

    PubMed  CAS  Google Scholar 

  20. Jenab, S. and Morris, P. L. (1996) Differential activation of signal transducer and activator of transcription (STAT)-3 and STAT-1 transcription factors and c-fos messenger ribonucleic acid by interleukin-6 and interferon-gamma in Sertoli cells. Endocrinology 137, 4738–4743.

    PubMed  CAS  Google Scholar 

  21. Tanaka, N., Asao, H., Ohbo, K., Ishu, N., Takeshita, T., Nakamura, M., et al. (1994) Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor beta and gamma chains. Proc. Natl. Acad. Sci. U. S. A. 91, 7271–7275.

    PubMed  CAS  Google Scholar 

  22. Takaki, S., Kanazawa, H., Shiiba, M., and Takatsu, K. (1994) A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Mol. Cell. Biol. 14, 7404–7413.

    PubMed  CAS  Google Scholar 

  23. Yin, Y., Yasukawa, K., Taga, T., Kishimoto, T., and Yang, Y. C. (1994) Identification of a 130-kilodalton tyrosine-phosphorylated protein induced by interleukin-11 as JAK2 tyrosine kinase, which associated with gp130 signal transducer. Exp. Hematol. 22, 467–472.

    PubMed  CAS  Google Scholar 

  24. Bacon, C. M., McVicar, D. W., Ortaldo, J. R., Rees, R. C., O'Shea, J. J., and Johnston, J. A. (1995) Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2 differential use of Janus family tyrosine kinases by IL-2 and IL-12. J. Exp. Med. 181, 399–404.

    PubMed  CAS  Google Scholar 

  25. Quelle, F. W., Sato, N., Witthuhn, B. A., Inhorn, R. C., Eder, M., Miyajima, A., et al. (1994) JAK2 associates with the beta c chain of the receptor for granulocyte macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol. Cell. Biol. 14, 4335–4341.

    PubMed  CAS  Google Scholar 

  26. Wang, Y. and Fuller, G. M. (1995) Interleukin-6 and ciliary neurotrophic factor trigger janus kinase activation and early gene response in rat hepatocytes. Gene 162, 285–289.

    PubMed  CAS  Google Scholar 

  27. Shimoda, K., Iwasaki, H., Okamura, S., Ohno, Y., Kubota, A., Arima, F., et al. (1994). G-CSF induces tyrosine phosphorylation of the JAK2 protein in the human myeloid G-CSF responsive and proliferative cells, but not in mature neutrophils. Biochem. Biophys. Res. Commun. 203, 922–928.

    PubMed  CAS  Google Scholar 

  28. Drachman, J. G., Griffin, J. D. and Kaushansky K. (1995) The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, She, and c-Mpl. J. Biol. Chem. 270, 4979–4982.

    PubMed  CAS  Google Scholar 

  29. Ghilardi, N., and Skoda, R. C. (1997) The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol. Endocrinol. 11, 393–399.

    PubMed  CAS  Google Scholar 

  30. Rodig, S. J., Meraz, M. A., White, J. M., Lampe, P. A., Riley, J. K., Arthur, C. D., et al. (1998) Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93, 373–383.

    PubMed  CAS  Google Scholar 

  31. Parganas, E., Wang, D., Stravopodis, D., Topham, D. J., Marine, J. C., Teglund, S., et al. (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93, 385–395.

    PubMed  CAS  Google Scholar 

  32. Neubauer, H., Cumano, A., Muller, M., Wu, H., Huffstadt, U., and Pfeffer, K. (1998) Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93, 397–409.

    PubMed  CAS  Google Scholar 

  33. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H., and Berg, L. J. (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794–797.

    PubMed  CAS  Google Scholar 

  34. Suzuki, K., Nakajima, H., Saito,Y., Saito, T., Leonard, W. J., Iwamoto, I. (2000) Janus kinase 3 (Jak3) is essential for common cytokine receptor gamma chain (gamma(c))-dependent signaling comparative analysis of gamma(c), Jak3, and gamma(c) and Jak3 double-deficient mice. Int. Immunol. 12, 123–132.

    PubMed  CAS  Google Scholar 

  35. Karaghiosoff, M., Neubauer, H., Lassnig, C., Kovarik, P., Schindler, H., Pircher, H., et al. (2000) Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13, 549–560.

    PubMed  CAS  Google Scholar 

  36. Meraz, M. A., White, J. M., Sheehan, K. C., Bach, E. A., Rodig, S. J., Dighe, A. S., et al. (1996) Targeted disruption of the Statl gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442.

    PubMed  CAS  Google Scholar 

  37. Park, C., Li, S., Cha, E., and Schindler, C. (2000) Immune response in Stat2 knockout mice. Immunity 13, 795–804.

    PubMed  CAS  Google Scholar 

  38. Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., et al. (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. U.S.A. 94, 3801–3804.

    PubMed  CAS  Google Scholar 

  39. Kaplan, M. H., Sun, Y. L., Hoey, T., and Grusby, M. J. (1996) IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382, 174–177.

    PubMed  CAS  Google Scholar 

  40. Wu, C., Wang, X., Gadina, M., O'Shea, J. J., Presky, D. H., and Magram, J. (2000) IL-12 receptor beta 2 (IL-12R beta 2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites. J. Immunol. 165, 6221–6228.

    PubMed  CAS  Google Scholar 

  41. Liu, X., Robinson, G. W., Wagner, K., Garrett, L., Wynshaw-Boris, A., and Hennighausen, L. (1997) Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 11, 179–186, 1997.

    PubMed  CAS  Google Scholar 

  42. Udy, G. B., Towers, R. P., Snell, R. G., Wilkins, R. J., Park, S. H., Ram, P. A., et al. (1997) Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc. Natl. Acad. Sci. U.S.A. 94, 7239–7244.

    PubMed  CAS  Google Scholar 

  43. Teglund, S., McKay, C., Schuetz, E., van Deursen, J. M., Stravopodis, D., Wang, D., et al. (1998) Stat5a and Stat5b proteins have essential and nonessential. or redundant. roles in cytokine responses. Cell 93, 841–850.

    PubMed  CAS  Google Scholar 

  44. Kaplan, M. H., Schindler, U., Smiley, S. T., and Grusby, M. J. (1996) Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313–319.

    PubMed  CAS  Google Scholar 

  45. Shimoda, K., van Deursen, J., Sangster, M. Y., Sarawar, S. R., Carson, R. T., Tripp, R. A., et al. (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380, 630–633.

    PubMed  CAS  Google Scholar 

  46. Heim, M. H., Kerr, I. M., Stark, G. R., and Darnell, J. E. Jr. (1995) Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267, 1347–1349.

    PubMed  CAS  Google Scholar 

  47. Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E. Jr. and Yancopoulos, G. D. (1995) Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267, 1349–1353.

    PubMed  CAS  Google Scholar 

  48. 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.

    PubMed  CAS  Google Scholar 

  49. VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., et al. (1994) Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase. J. Biol. Chem. 269, 21709–21717.

    PubMed  CAS  Google Scholar 

  50. Wen, Z., Zhong, Z., and Darnell, J. E., Jr. (1995) Maximal activation of transcription by Statl and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250.

    PubMed  CAS  Google Scholar 

  51. Wen, Z. and Darnell, J. E., Jr. (1997) Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Statl and Stat3. Nucleic. Acids. Res. 25, 2062–2067.

    PubMed  CAS  Google Scholar 

  52. 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 

  53. 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.

    PubMed  CAS  Google Scholar 

  54. Sayeski, P. P., Ali, M. S., Hawks, K., Frank, S. J., and Bernstein, K. E. (1999) The angiotensin II-dependent association of Jak2 and c-Src requires the N-terminus of Jak2 and the SH2 domain of c-Src. Circ. Res. 84, 1332–1338.

    PubMed  CAS  Google Scholar 

  55. Chauhan, D., Kharbanda, S. M., Ogata, A., Urashima, M., Frank, D., Malik, N. et al. (1995) Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. J. Exp. Med. 182, 1801–1806.

    PubMed  CAS  Google Scholar 

  56. Fuhrer, D. K. and Yang, Y. C. (1996) Complex formation of JAK2 with PP2A, P13K. and Yes in response to the hematopoietic cytokine interleukin-11. Biochem. Biophys. Res. Comm. 224, 289–296.

    PubMed  CAS  Google Scholar 

  57. Xia, K., Mukhopadhyay, N. K., Inhorn, R. C., Barber, D. L., Rose, P. E., Lee, R. S., et al. (1996) The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Proc. Natl. Acad. Sci. U. S. A. 93, 11681–11686.

    PubMed  CAS  Google Scholar 

  58. VanderKuur, J., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1995) Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2, J. Biol. Chem. 270, 7587–7593.

    PubMed  CAS  Google Scholar 

  59. Fuhrer, D. K., Feng, G. S., and Yang, Y. C. (1995) Syp associates with gp130 and Janus kinase 2 in response to interleukin-11 in 3T3-L1 mouse preadipocytes. J. Biol. Chem. 270, 24826–24830.

    PubMed  CAS  Google Scholar 

  60. Zhu, T., Goh, E. L., and Lobie, P. E., (1998) Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2 Fak is not required for stat-mediated transcription. J. Biol. Chem. 273, 10682–10689.

    PubMed  CAS  Google Scholar 

  61. Bhat, G. J., Thekkumkara, T. J., Thomas, W. G., Conrad, K. M., and Baker, K. M. (1994) Angiotensin II stimulates sis-inducing factor-like DNA binding activity Evidence that the AT1A receptor activates transcription factor-Stat91 and or a related protein. J. Biol. Chem. 269, 31443–31449.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  63. 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 signalling proteins in plasmalemmal caveolae. Biochem. J. 351, 257–264.

    PubMed  CAS  Google Scholar 

  64. 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.

    PubMed  CAS  Google Scholar 

  65. 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 

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

    PubMed  CAS  Google Scholar 

  67. Sasaguri, T., Teruya, H., Ishida, A., Abumiya, T., and Ogata, J. (2000) Linkage between a1 adrenergic receptor and the Jak/Stat signaling pathway in vascular smooth muscle cells. Biochem. Biophys. Res. Comm. 268, 25–30.

    PubMed  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  70. Ali, M. S., Sayeski, P. P., and Bernstein, K. E. (2000) Jak2 acts as both a STAT1 kinase and as a molecular bridge linking STAT1 to the angiotensin II AT1 receptor. J. Biol. Chem. 275, 15586–15593.

    PubMed  CAS  Google Scholar 

  71. Frank, S. J. (2001) Growth hormone signalling and its regulation preventing too much of a good thing. Growth Horm. J. G. F. Res. 11, 201–212.

    CAS  Google Scholar 

  72. Park, O. K., Schaefer, T. S., and Nathans, D. (1996) In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc. Natl. Acad. Sci. U. S. A. 93, 13704–13708.

    PubMed  CAS  Google Scholar 

  73. 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 

  74. Rui, L. and Carter-Su, C. (1999) Identification of SH2-Bb as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2. Proc. Natl. Acad. Sci. U. S. A. 96, 7172–7177.

    PubMed  CAS  Google Scholar 

  75. Saxton, T. M., Henkemeyer, M., Gasca, S., Shen, R., Rossi, D. J., Shalaby, F. et al. (1997) Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 16, 2352–2364.

    PubMed  CAS  Google Scholar 

  76. Kim, S. O., Jiang, J., Yi, W., Feng, G. S., and Frank, S. J. (1998) Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. J. Biol. Chem. 273, 2344–2354.

    PubMed  CAS  Google Scholar 

  77. You, M., Yu, D. H., and Feng, G. S. (1999) Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/ STAT pathway. Mol. Cell. Biol. 19, 2416–2424.

    PubMed  CAS  Google Scholar 

  78. 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.

    PubMed  CAS  Google Scholar 

  79. Duhe, R. J. and Farrar, W. L. (1995) Characterization of active and inactive forms of JAK2 protein-tyrosine kinase produced via the baculovirus expression vector system. J. Biol. Chem. 270, 23084–23089.

    PubMed  CAS  Google Scholar 

  80. Zhuang, H., Patel, S. V., He, T. C., Niu, Z., and Wojchowski, D. M. (1994) Dominant negative effects of a carboxy-truncated JaK2 mutant on Epo-induced proliferation and Jak2 activation Biochem. Biophys. Res. Commun. 204, 278–283.

    PubMed  CAS  Google Scholar 

  81. Zhuang, H., Patel, S. V., He, T. C., Sonsteby, S. K., Niu, Z., and Wojchowski, D. M. (1994) Inhibition of erythropoietin-induced mitogenesis by a kinase-deficient form of Jak2. J. Biol. Chem. 269, 2141–21414.

    Google Scholar 

  82. Cools, J., Peeters, P., Voet, T., Aventin, A., Mecucci, C., Grandchamp, B., et al. (1999) Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. Cytogener. Cell. Genet. 85, 260–266.

    CAS  Google Scholar 

  83. Jiao, H., Berrada, K., Yang, W., Tabrizi, M., Platanias, L. C., and Yi, T. (1996) Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol. Cell. Biol. 16, 6985–6992.

    PubMed  CAS  Google Scholar 

  84. Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., et al. (1993). Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454.

    PubMed  CAS  Google Scholar 

  85. Tsui, H. W., Siminovitch, K. A., de Souza, L., and Tsui, F. W. (1993). Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat. Genet. 4, 124–129.

    PubMed  CAS  Google Scholar 

  86. Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., et al. (1995) Anovel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosinephosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 14, 2816–2826.

    PubMed  CAS  Google Scholar 

  87. Yasukawa, H., Misawa, H., Sakamoto, H., Masuhara, M., Sasaki, A., Wakioka, T., et al. (1999) The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 18, 1309–1320.

    PubMed  CAS  Google Scholar 

  88. Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P., et al. (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278, 1803–1805.

    PubMed  CAS  Google Scholar 

  89. Liu, B., Liao, J., Rao, X., Kushner, S. A., Chung, C. D., Chang, D. D., and Shuai, K. (1998) Inhibition of Statl-mediated gene activation by PIASI. Proc. Natl. Acad. Sci. U. S. A. 95, 10626–10631.

    PubMed  CAS  Google Scholar 

  90. Yoshikawa, H., Matsubara, K., Qian, G. S., Jackson, P., Groopman, J. D., Mann, J. E., et al. (2001) SOCS-1, a negative regulator of the JAK/ STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat. Genet. 1, 29–35.

    Google Scholar 

  91. Real, P. J., Sierra, A., De Juan, A., Segovia, J. C., Lopez-Vega, J. M., and Fernandez-Luna, J. L. (2002) Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene 50, 7611–7618.

    Google Scholar 

  92. Xie, S., Lin, H., Sun, T., and Arlinghaus, R. B. (2002) Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 47, 7137–7146.

    Google Scholar 

  93. Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., et al. (1996) Inhibition of acute lymphoblastic leukemia by a Jak-2 inhibitor. Nature 379, 645–648.

    PubMed  CAS  Google Scholar 

  94. Yamauchi, T., Yamauchi, N., Ueki, K., Sugiyama, T., Waki, H., Miki, H., et al. (2000) Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 autocrine secretion of prolactin in human breast cancer. J. Biol. Chem 275, 33937–33944.

    PubMed  CAS  Google Scholar 

  95. Miyamoto, N., Sugita, K., Goi, K., Inukai, T., Lijima, K., Tezuka, T., et al. (2001) The Jak2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Phyladelphia chromosome. Leukemia 11, 1758–1768.

    Google Scholar 

  96. Seki, Y., Kai, H., Shibata, R., Nagata, T., Yasukawa, H., Yosimura, A., et al. (2000) Role of the JAK/ STAT pathway in rat carotid artery remodeling after vascular injury. Circ. Res. 87, 12–18.

    PubMed  CAS  Google Scholar 

  97. Kodama, H., Fukuda, K., Pan, J., Sano, M., Takahashi, T., Kato, T., et al. (2000) Significance of ERK cascade compared with JAK/ STAT and P13-K pathway in gp-130-mediated cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 279, H1635–644.

    PubMed  CAS  Google Scholar 

  98. El-Adawi, H., Deng, L., Tramontano, A., Smith, S., Mascareno, E., Ganguly, K., et al. (2003) The functional role of the JAK-STAT pathway in post-infarction remodeling. Cardiovasc. Res. 57, 129–138.

    PubMed  CAS  Google Scholar 

  99. Mascareno, E., El-Shafei, M., Maulik, N., Sato, M., Guo, Y., Das, D. K., et al. (2001) JAK/ STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion. Circulation 104, 325–329.

    PubMed  CAS  Google Scholar 

  100. Kleinberger-Doron, N., Shelah, N., Capone, R., Gazit, A., and Levitzki, A. (1998) Inhibition of Cdk2 activation by selected tyrphostins causes cell cycle arrest at late G1 and S phase. Exp. Cell Res. 241, 340–351.

    PubMed  CAS  Google Scholar 

  101. Oda, Y., Renaux, B., Bjorge, J., Saifeddine, M., Fujita, D. J., and Hollenberg, M. D. (1999) sSrc is a major cytosolic tryrosine kinase in vascular tissue. Can. J. Physiol. Pharmacol. 77, 606–617.

    PubMed  CAS  Google Scholar 

  102. Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993) Selective inhibition of the EGF and HER2/ Neu receptors by tyrphostins. J. Biol. Chem. 268, 11134–11142.

    PubMed  CAS  Google Scholar 

  103. Gu, Y., Zou, Y., Aikawa, R., Hayashi, D., Kudoh, S., Yamauchi, T., et al. (2001) Growth hormone signalling and apoptosis in neonatal rat cardiomyocytes. Mol. Cell. Biochem. 223, 35–46.

    PubMed  CAS  Google Scholar 

  104. VonDerLinden, D., Ma, X., Sandberg, E. M., Gernert, K., Bernstein, K. E., and Sayeski, P. P. (2002) Mutation of glutamic acid residue 1046 abolishes Jak2 tyrosine kinase activity. Mol. Cell. Biochem. 241, 87–94.

    PubMed  CAS  Google Scholar 

  105. Frank, S. J., Yi, W., Zhao, Y., Goldsmith, J. F., Gilliland, G., Jiang, J., et al (1995) Regions of the Jak2 tyrosine kinase required for coupling to the growth hormone receptor. J. Biol. Chem. 270, 14776–14785.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  107. 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 

  108. Lindauer, K., Loerting, T., Liedl, K. R., and Kroemer, R. T. (2001) Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Engineering 14, 27–37.

    PubMed  CAS  Google Scholar 

  109. Chen, M., Cheng, A., Candotti, F., Zhou, Y-J., Hymel, A., Fasth, A., et al. (2000) Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: evidence for interactions between the kinase and pseudokinase domains. Mol. Cell. Biol. 20, 947–956.

    PubMed  CAS  Google Scholar 

  110. 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.

    PubMed  CAS  Google Scholar 

  111. Saharinen, P., Vihinen, M., and Silvennoinen, O. (2003) Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol. Biol. Cell 14, 1448–1459.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  114. 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.

    PubMed  CAS  Google Scholar 

  115. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  117. Leto, T. L. and Marchesi, V. T. (1984) A structural model of human erythrocyte protein 4.1. J. Biol. Chem. 259, 4603–4608.

    PubMed  CAS  Google Scholar 

  118. Banville, D., Ahmad, S., Stocco, R., and Shen, S. H. (1994) A novel protein-tyrosine phosphatase with homology to both the cytoskeletal proteins of the band 4.1 family and junction associated guanylate kinases. J. Biol. Chem. 269, 22320–22327.

    PubMed  CAS  Google Scholar 

  119. Schaller, M. D., Borgman, C. A., Cobb, B. S., Vines, R. R., Reynolds, A. B., et al (1992) pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl. Acad. Sci. U.S.A. 89, 5192–5196.

    PubMed  CAS  Google Scholar 

  120. Ynemura, 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.

    Google Scholar 

  121. 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.

    PubMed  CAS  Google Scholar 

  122. 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

    PubMed  CAS  Google Scholar 

  123. Chen, M., Cheng, A., Chen, Y. Q., Hymel, A. Hanson, E. P., Kimmel, L., et al. (1997) The amino terminus of Jak3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. Proc. Natl. Acad. Sci. U. S. A 94, 6910–6915

    PubMed  CAS  Google Scholar 

  124. 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 

  125. Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B., and Castelli, W. P. (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N. Engl. J. Med. 322, 1561–1566.

    Article  PubMed  CAS  Google Scholar 

  126. Zak, R. (1984) Factors controlling cardiac growth, in Growth of the Heart in Health and Disease (Zak, R., ed.), Raven, NY, pp. 165–185.

    Google Scholar 

  127. Casale, P. N., Devereux, R. B., Milner, M., Zullo, G., Harshfield, G. A., Pickering, T. G., et al. (1986) Value of echocardiographic measurument of left ventricular mass in predicting cardiovascular morbid events in hypertensive men. Ann. Intern. Med. 105, 173–178.

    PubMed  CAS  Google Scholar 

  128. Zimmer, H. G., Kolbeck-Ruhmkorff, C., and Zierhut, W. (1995) Cardiac hypertrophy induced by alpha- and beta-adrenergic receptor stimulation. Cardioscience 6, 47–57.

    PubMed  CAS  Google Scholar 

  129. Komuro, I., Kaida, T., Shibazaki, Y., Kurabayashi, M., Katoh, Y., Hoh, E., et al. (1990) Stretching cardiac myocytes stimulates protooncogene expression. J. Biol. Chem. 265, 3595–3598.

    PubMed  CAS  Google Scholar 

  130. Sadoshima, J. and Izumo, S. (1993) Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes potential involvement of autocrine/paracrine mechanism. EMBO J. 12, 1681–1692

    PubMed  CAS  Google Scholar 

  131. Rozich, J. D., Barnes, M. A., Schmid, P. G., Zile, M. R., McDermott, P. J., and Cooper, G. 4th. (1995) Load effects on gene expression during cardiac hypertrophy. J. Mol. Cell. Cardiol. 27, 485–499.

    PubMed  CAS  Google Scholar 

  132. Komuro, I., Kudo, S., Yamazaki, T., Zou, Y., Shiojima, I., and Yazaki, Y. (1996) Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes. FASEB J. 10, 631–636.

    PubMed  CAS  Google Scholar 

  133. Yamaziki, T., Tobe, K., Hoh, E., Maemura, K., Kaida, T., Komuro, I., et al. (1993) Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. J. Biol. Chem. 268, 12069–12076.

    Google Scholar 

  134. Sadoshima, J., Xu, Y., Slayter, H. S., and Izumo, S. (1993). Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, 977–984

    PubMed  CAS  Google Scholar 

  135. Ito, H., Hirata, Y., Adachi, S., Tanaka, M., Tsujino, M., Koike, A., et al. (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. Circ. Res. 81, 656–663.

    Google Scholar 

  136. Kodama, H., Fukada, K., Pan, J., Makino, S., Baba, A., Hori, S., et al. (1997) Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in cardiomyocytes. Circ. Res. 81, 656–663.

    PubMed  CAS  Google Scholar 

  137. Kunisada, K., Hirota, H., Fujio, Y., Matsui, H., Tani, Y., Yamauchi-Takihara, K., et al. (1996) Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation 94, 2626–2632.

    PubMed  CAS  Google Scholar 

  138. Pennica, D., Wood, W. I., and Chien, K. R. (1996) Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp130 dependent pathways. Cytokine Growth Factor Rev. 7, 81–91.

    PubMed  CAS  Google Scholar 

  139. Pan, J., Keiichi, F., Hiroaki, K., Shinji, M., Toshiyuki, T., Motoaki, S., et al. (1997) Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circ. Res. 81, 611–617.

    PubMed  CAS  Google Scholar 

  140. Pan, J., Fukuda, K., Kodama, H., Sano, M., Takahashi, T., Makino, S., et al. (1998) Involvement of gp 130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. Heart Vessels 13, 199–208.

    PubMed  CAS  Google Scholar 

  141. Pan, J., Fukudo, K., Saito, M., Matsuzaki, J., Kodama, H., Sano, M., et al. (1999) Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ. Res. 84, 1127–1136.

    PubMed  CAS  Google Scholar 

  142. Pennica, D., King, K. L., Shaw, K. J., Luis, E., Rullamas, J., Luoh, S. M., et al. (1995) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc. Natl. Acad. Sci. U. S. A 92, 1142–1146.

    PubMed  CAS  Google Scholar 

  143. Pennica, D., Shaw, K. J., Swanson, T. A., Moore, M. W., Shelton, D. L., Zioncheck, K. A., et al. (1995) Cardiotrophin-1: biological activities and binding to the leukemia inhibitory factor receptor/gp 130 signaling complex. J. Biol. Chem. 270, 10915–10922.

    PubMed  CAS  Google Scholar 

  144. Fukuzawa, J., Booz, G. W., Hunt, R. A., Shimizu, N., Karoor, V., Baker, K. M., et al. (2000) Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3: an autocrine loop for hypertrophy. Hypertension 35, 1191–1196.

    PubMed  CAS  Google Scholar 

  145. Hunter, J. J. and Chien, K. R. (1999) Signaling pathways for cardiac hypertrophy and failure. N. Engl. J. Med. 341, 1276–1283.

    PubMed  CAS  Google Scholar 

  146. Podewski, E. K., Hilfiker-Kleiner, D., Hilfiker, A., Moraweitz, H., Lichtenberg, A., Wollert, K. C., et al. (2003) Alterations in janus kinase (JAK)-signal transducers and activators of transcription (STAT) signalling in patients with end-stage dilated cardiomyopathy. Circulation 107, 798–802.

    PubMed  CAS  Google Scholar 

  147. Murry, C. E., Jennings, R. B. and Reimer, K. A. (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136.

    PubMed  CAS  Google Scholar 

  148. Bolli, R. (2000) The late phase of preconditioning. Circ. Res. 87, 972–983.

    PubMed  CAS  Google Scholar 

  149. Kuzuya, T., Hoshida, S., Yamashita, N., Fuji, H., Oe, H., Hori, M., et al. (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ. Res. 72, 1293–1299.

    PubMed  CAS  Google Scholar 

  150. Marber, M. S., Latchman, D. S., Walker, J. M., and Yellon, D. M. (1993) Cardiac stress protein elevation 24 hours after brief ischemic or heat stress is associated with resistance to myocardial infarction. Circulation 88, 1264–1272.

    PubMed  CAS  Google Scholar 

  151. Sun, J. Z, Tang, X. L., Park, S. W., Qiu, Y., Turrens, J. F., and Bolli, R. (1996) Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs. J. Clin. Invest. 97, 562–576.

    Article  PubMed  CAS  Google Scholar 

  152. Hattori, R., Maulik, N., Otani, H., Zhu, L., Cordis, G., Engelman, R. M., et al. (2001) Role of STAT3 in ischemic preconditioning. J. Mol. Cell. Cardiol. 33, 1929–1936.

    PubMed  CAS  Google Scholar 

  153. Guo, Y., Jones, W. K., Xuan, Y. T., Tang, X. L., Bao, W., Wu, W. J., et al. (1999) The late phase of ischemic preconditioning is abrogated by targeted disruption of the iNOS gene. Proc. Natl. Acad. Sci. U. S. A. 96, 11507–11512.

    PubMed  CAS  Google Scholar 

  154. Shinmura, K., Tang, X. L., Wang, Y., Xuan, Y. T., Liu, S. Q., Takano, H., et al. (2000) Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc. Natl. Acad. Sci. U. S. A. 97, 10197–10202.

    PubMed  CAS  Google Scholar 

  155. Shinmura, K., Bolli, R., Liu, S. Q., Tang, X. L., Kodani, E., Xuan, Y. T., et al. (2002) Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circ. Res. 91, 240–246.

    PubMed  CAS  Google Scholar 

  156. Xuan, Y. T., Guo, Y., Han, H., Zhu, Y., and Bolli, R. (2001) An essential role of the JAKSTAT pathway in ischemic preconditioning. Proc. Natl. Acad. Sci. U. S. A. 98, 9050–9055.

    PubMed  CAS  Google Scholar 

  157. Xuan, Y. T., Guo, Y., Zhu, Y., Han, H., Langenbach, R., Dawn, B., et al (2003) Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J. Mol. Cell. Cardiol. 35, 525–537.

    PubMed  CAS  Google Scholar 

  158. 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 

  159. 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.

    PubMed  CAS  Google Scholar 

  160. 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 

  161. 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 

  162. 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 

  163. 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 

  164. Kim, S. O., Houtman, J. C., Jiang, J., Ruppert, J. M., Bertics, P. J., and Frank, S. J. (1999) Growth hormone-induced alteration in ErbB-2 phosphorylation status in 3T3-F442a fibroblasts. J. Biol. Chem. 274, 36015–36024.

    PubMed  CAS  Google Scholar 

  165. Gao, B., Shen, X., Kunos, G., Meng, Q., Goldberg, I. D., Rosen, E. M., et al. (2001) Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. FEBS Lett. 488, 179–184.

    PubMed  CAS  Google Scholar 

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  1. Department of Physiology and Functional Genomics, University of Florida College of Medicine, P.O. Box 100274, 32610, Gainesville, FL

    Eric M. Sandberg, Tiffany A. Wallace, Michael D. Godeny, Danielle VonDer Linden & Peter P. Sayeski

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Sandberg, E.M., Wallace, T.A., Godeny, M.D. et al. Jak2 tyrosine kinase. Cell Biochem Biophys 41, 207–231 (2004). https://doi.org/10.1385/CBB:41:2:207

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