Skip to main content
SpringerLink
Log in

Jak family of kinases in cancer

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

The family of Jak kinases is composed from at least four different tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share significant structural homology with each other. The members of this family of kinases associate constitutively with a variety of cytokine and hormone receptors. Upon binding of the specific ligands to their receptors, Jak kinases are rapidly activated and their kinase activities induced, to regulate tyrosine phosphorylation of various effectors and initiate activation of downstream signaling pathways. The discovery of this family of tyrosine kinases dates back in the early 1990s with the cloning of the Tyk-2 tyrosine kinase as a critical element of the Type I interferon signaling pathway. Extensive work over the last few years has provided evidence that Jak kinases play important roles in the generation of responses for interferons, which are cytokines that exhibit important antitumor activities. There is also accumulating evidence that constitutive activation of different Jaks and Stats mediates neoplastic transformation and promotes abnormal cell proliferation in various malignancies. This review summarizes the role of various Jak-kinase dependent pathways in malignancies and discusses the therapeutic implications of the recent advances in the field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Schindler CW: Series introduction JAK-STAT signaling in human disease. J Clin Invest 109: 1133–1137, 2002

    Google Scholar 

  2. Rane SG, Reddy EP: Janus kinases: components of multiple signaling pathways. Oncogene, 19: 5662–5679, 2000

    Google Scholar 

  3. Leonard WJ, O'shea JJ: Jaks and STATs. Biological implications. Ann Rev Immunol 16: 293–322, 1998

    Google Scholar 

  4. Darnell JE Jr, Kerr IM, Stark GR: Jak-Stat pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421, 1994

    Google Scholar 

  5. Ihle JN: The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv Immunol 6: 1–35, 1995

    Google Scholar 

  6. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider B, Silvennoinen O: Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci 19: 222–227, 1994

    Google Scholar 

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

    Google Scholar 

  8. Darnell JE Jr: Stats and gene regulation. Science 277: 1630–1635, 1997

    Google Scholar 

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

    Google Scholar 

  10. Yeh TC, Pellegrini S: The Janus kinase family of protein tyrosine kinases and their role in signaling. Cell Mol Life Sci 55: 1523–1534, 1999

    Google Scholar 

  11. Velazquez L, Fellous M, StarkGR, Pellegrini S: A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell 70: 313–322, 1992

    Google Scholar 

  12. Pestka S, Langer JA, Zoon KC, Samuel CE: Interferons and their actions. Annu Rev Biochem 56: 727–777, 1987

    Google Scholar 

  13. Platanias LC: Interferons. Laboratory to clinic investigations. Curr Opin Oncol 7: 560–565, 1995

    Google Scholar 

  14. Gutterman JU: Cytokine therapeutics: Lessons from interferon a. Proc Natl Acad Sci USA 91: 1198–1205, 1994

    Google Scholar 

  15. Platanias LC, Fish EN: Signaling pathways activated by interferons. Exp Hematol 27: 1583–1592, 1999

    Google Scholar 

  16. Müller M, Briscoe J, Laxton C, Guschin D, Ziemecki A, Silvennoinen O, Harpur AG, Barbieri G, Witthu BA, Schindler C, Pellegrini S, Wilks AF, Ihle JN, Stark GR, Kerr IM: The protein tyrosine kinase JAK-1 complements defects in interferon a/b signal transduction. Nature 366: 129–135, 1993

    Google Scholar 

  17. Silvenoinen O, Ihle JN, Schlessinger J, Levy DE: Interferon-induced nuclear signaling by Jakprotein tyrosine kinases. Nature 366: 583–585, 1993

    Google Scholar 

  18. Colamonici OR, Uyttendaele H, Domanski P, Yan H, Krolewski JJ: p135tyk2 an interferon-dependent tyrosine kinase, is physically associated with an interferon receptor. J Biol Chem 269: 3518–3522, 1994

    Google Scholar 

  19. Domanski P, Fish E, Nadeau OW, Witte M, Platanias LC, Yan H, Krolewski J, Pitha P, and Colamonici OR: A region of the beta subunit of the interferon alpha receptor different from box 1 interacts with Jak1 and is sufficient to activate the Jak-stat pathway and induce an antiviral state. J Biol Chem 272: 26388–26393, 1997

    Google Scholar 

  20. Platanias LC, Uddin S, Colamonici OR: Tyrosine phosphorylation of the a and b subunits of the Type I Interferon receptor. Interferon b selectively induces tyrosine phosphorylation of an a subunit associated protein. J Biol Chem 27: 17761–17764, 1994

    Google Scholar 

  21. Levy DE, Kessler DS, Pine R, Reich N, Darnell JE Jr: Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative control. Genes Dev 2: 383–393, 1988

    Google Scholar 

  22. Gribambo GE, Toniato E, Engel DA, Lengyel P: Interferons as gene activators. Characteristics of an interferon-activatable enhancer. J Biol Chem 262: 11878–11883, 1987

    Google Scholar 

  23. Reich N, Evans B, Levy D, Fahey D, Knight E, Darner JE Jr: Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci USA 84: 6394–6398, 1987

    Google Scholar 

  24. Levy DE, Kessler DS, Pine R, Darnell JE Jr: Cytoplasmic activation of ISGF3, the positive regulator of interferonstimulated transcription, reconstituted in vitro. Genes Dev 3: 1362–1371, 1989

    Google Scholar 

  25. Fu X-Y: A transcription factor with SH2 and SH3 domains is directly activated by an interferon-induced cytoplasmic tyrosine kinase(s). Cell 70: 323–335, 1992

    Google Scholar 

  26. Schindler C, Shuai K, Prezioso VR, Darnell JE Jr: Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic factor. Science 257: 809–813, 1992

    Google Scholar 

  27. Gutch MJ, Daly C, Reich NC: Tyrosine phosphorylation is required for activation of an interferon-stimulated transcription factor. Proc Natl Acad Sci USA 8: 11411–11415, 1992

    Google Scholar 

  28. StarkGR, Kerr IM, Williams BRG, Silverman RH, Schreiber RD: How cells respond to interferons. Ann Rev Biochem 67: 227–264, 1998

    Google Scholar 

  29. Meinke A, Barahmand-Pour F, Wohrl S, Stoiber D, Decker T: Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons. Mol Cell Biol 16: 6937–6944, 1996

    Google Scholar 

  30. Uddin S, Yenush L, Sun X-J, Sweet ME, White MF, Platanias LC: Interferon a engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 30-kinase. J Biol Chem 270: 15938–15941, 1995

    Google Scholar 

  31. Platanias LC, Uddin S, Yetter A, Sun X-J, White MF: The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. J Biol Chem 271: 278–282, 1996

    Google Scholar 

  32. Uddin S, Fish EN, Sher D, Gardziola C, Colamonici OR, Kellum M, Pitha P, White MF, Platanias LC: The IRSpathway operates distinctively from the Stat-pathway in hematopoietic cells and transduces common and distinct signals during engagement of the insulin or IFNa receptors. Blood 90: 2574–2582, 1997

    Google Scholar 

  33. Uddin S, Fish EN, Sher DA, Gardziola C, White MF, Platanias LC: Activation of the phosphatidylinositol 3′-kinase serine kinase by IFNa. J Immunol 158: 2390–2397, 1997

    Google Scholar 

  34. Platanias LC, Sweet ME: Interferon a induces rapid tyrosine phosphorylation of the vav proto-oncogene product in hematopoietic cells. J Biol Chem 269: 3143–3146, 1994

    Google Scholar 

  35. Uddin S, Sweet ME, Colamonici OR, Krolewski JJ, Platanias LC: The vav proto-oncogene product interacts with the Tyk-2 tyrosine kinase. FEBS Lett 403: 31–34, 1997

    Google Scholar 

  36. Micouin A, Wietzrbin J, Steunou V, Martyre MC: p95Vav is associated to the IFNα/β receptor and contributes to the antiproliferative effect of IFNa in megacaryocytic cell lines. Oncogene 19: 387–394, 2000

    Google Scholar 

  37. Adam L, Bandyopathy D, Kumar R: Interferon-alpha signaling promotes nucleus to cytoplasmic redistribution of p95Vav and formation of a multisubunit complex involving Vav, Ku80, and Tyk2. Biochem Biophys Res Commun 267: 692–696, 2000

    Google Scholar 

  38. Ahmad S, Alsayed Y, Druker BJ, Platanias LC: The Type I interferon receptor mediates tyrosine phos-phorylation of the CrkL adaptor protein. J Biol Chem 272: 29991–29994, 1997

    Google Scholar 

  39. Fish EN, Uddin S, Korkmaz M, Majchrzak B, Druker BJ, Platanias LC: Activation of a CrkL-Stat5 signaling complex by Type I interferons. J Biol Chem 274: 571–573, 1999

    Google Scholar 

  40. Grumbach IM, Mayer IA, Uddin S, Lekmine F, Majchrzak B, Yamauchi H, Fujita S, Druker BJ, Fish EN, Platanias LC: Engagement of the CrkL adapter in interferon a signaling in BCR-ABL expressing cells. Br J Haematol 112: 327–336, 2001

    Google Scholar 

  41. Platanias LC, Uddin S, Bruno E, Korkmaz M, Ahmad S, Alsayed Y, Van Den Berg D, Druker BJ, Wickrema A, Hoffnan R: CrkL and CrkII participate in the generation of the growth inhibitory effects of interferons on primary hematopoietic progenitors. Exp Hematol 27: 1315–1321, 1999

    Google Scholar 

  42. Uddin S, MazchrzakB, Woodson J, Arunkumar P, Alsayed Y, Pine R, Young PR, Fish EN, Platanias LC: Activation of the p38 Map kinase by Type I IFNs. J Biol Chem 274: 30127–30131, 1999

    Google Scholar 

  43. Uddin S, Sharma N, Majchrzak B, Mayer I, Lekmine F, Young PR, Bokoch GM, Fish EN, Platanias LC: The Rac1/p38 Map kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J Biol Chem 275: 27634–27640, 2000

    Google Scholar 

  44. Mayer IA, Verma A, Grumbach IM, Uddin S, Lekmine F, Ravandi F, Majchrzak B, Fujita S, Fish EN, Platanias LC: The p38 Map kinase pathway mediates the growth inhibitory effects of IFNα in BCR-ABL expressing cells. J Biol Chem 276: 28570–28577, 2001

    Google Scholar 

  45. Verma A, Deb DK, Sassano A, Uddin S, Varga J, Wickrema A, Platanias LC: Activation of the p38 Map kinase pathway mediates the suppressive effects of Type I interferons and transforming growth factor beta on normal hematopoiesis. J Biol Chem 277: 7726–7735, 2002

    Google Scholar 

  46. Bach EA, Tanner JW, Marsters S, Ashkenazi A, Aguet M, Shaw AS, Schreiber RD: Ligand-induced assembly and activation of the gamma interferon receptor in intact cells. Mol Cell Biol 16: 3214, 1996

    Google Scholar 

  47. Sakatsume M, Igarashi K, Winestock KD, Garotta G, Larner AC, Finbloom DS: The Jakk inases differentially associate with the alpha and beta (accessory factor) chains of the interferon gamma receptor to form a functional receptor unit capable of activating STAT transcription factors. J Biol Chem 270: 17528, 1995

    Google Scholar 

  48. Kaplan DH, Greenlund AC, Tanner JW, Shaw AS, Schreiber RD: Identification of an interferon-gamma receptor alpha chain sequence required for JAK-1 binding. J Biol Chem 271: 9, 1996

    Google Scholar 

  49. Greenlund AC, Farrar MA, Viviano BL, Schreiber RD: Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J 13: 1591, 1994

    Google Scholar 

  50. Greenlund AC, Morales MO, Viviano BL, Yan H, Krolewski J, Schreiber RD: Stat recruitment by tyrosinephosphorylated cytokine receptors: An ordered reversible affinity-driven process. Immunity 2: 677, 1995

    Google Scholar 

  51. Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE: Polypeptide signaling to the nucleus through tyrosine phosphorylation of Jakand Stat proteins. Nature 366: 580–583, 1993

    Google Scholar 

  52. Shuai K, StarkGR, Kerr IM, Darnell JE Jr: A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science 261: 1744, 1993

    Google Scholar 

  53. Shuai K, Schindler C, Prezioso VR, Darnell JE Jr: Activation of transcription by IFN-gamma: Tyrosine phosphorylation of a 91-kD DNA binding protein. Science 258: 1808, 1992

    Google Scholar 

  54. Stephens JM, Lumpkin SJ, Fishman JB: Activation of signal transducers and activators of transcription 1 and 3 by leukemia inhibitory factor, oncostatin-M, and interferon-gamma in adipocytes. J Biol Chem 273: 31408, 1998

    Google Scholar 

  55. Alsayed Y, Uddin S, Ahmad S, Majchrzak B, Druker BJ, Fish EN, Platanias LC: Interferon g activates the C3GRap1 signaling pathway. J Immunol 164: 1800–1806, 2000

    Google Scholar 

  56. English BK, OrlicekSL, Mei Z, Meals EA: Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in macrophages: Evidence for involvement of the hck tyrosine kinase. J Leukoc Biol 62: 859, 1997

    Google Scholar 

  57. Nguyen H, Ramana CV, Bayes J, StarkGR: Role of phosphatidylinositol 3′-kinase in interferon-g-dependent phosphorylation of Stat1 on serine 727 and activation of gene expression. J Biol Chem 276: 33361, 2001

    Google Scholar 

  58. Uddin S, Sher D, Alsayed Y, Pons S, Colamonici OR, Fish EN, White MF, Platanias LC: Interaction of p59fyn with interferon-activated Jakk inases. Biochem Biophys Res Comm 235: 83–88, 1997

    Google Scholar 

  59. Uddin S, Grumbach I, Yi T, Colamonici OR, Platanias LC: Interferon α activates the tyrosine kinase Lyn in hematopoietic cells. Br J Haematol 101: 446–449, 1998

    Google Scholar 

  60. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'shea JJ: Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 370: 151–153, 1994

    Google Scholar 

  61. Liu KD, Gaffen SL, Goldsmith MA, Greene WC: Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Curr Biol 7: 817–261, 1997

    Google Scholar 

  62. Mizuguchi R, Hatakeyama M: Conditional activation of Janus kinase (JAK) confers factor independence upon interleukin-3-dependent cells. Essential role of Ras in JAK-triggered mitogenesis. J Biol Chem 273: 32297–32303, 1998

    Google Scholar 

  63. Keegan AD, Johnston JA, Tortolani PJ, McReynolds LJ, Kinzer C, O'shea JJ, Paul WE: Similarities and differences in signal transduction by interleukin 4 and interleukin 13: analysis of Janus kinase activation. Proc Natl Acad Sci USA 92: 7681–7685, 1995

    Google Scholar 

  64. Nielsen M, Nissen MH, Gerwien J, Zocca MB, Rasmussen HM, Nakajima K, Ropke C, Geisler C, Kaltoft K, Odum N: Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3. Blood 99: 973, 2002

    Google Scholar 

  65. Bellido T, Borba VZ, Roberson P, Manolagas SC: Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. Endocrinology 138: 3666–3676, 1997

    Google Scholar 

  66. Zeng YX, Takahashi H, Shibata M, Hirokawa K: JAK3 Janus kinase is involved in interleukin 7 signal pathway. FEBS Letters 353: 289–293, 1994

    Google Scholar 

  67. Tanuma N, Shima H, Nakamura K, Kikuchi K: Protein tyrosine phosphatase epsilonC selectively inhibits interleukin-6-and interleukin-10-induced JAK-STAT signaling. Blood 98: 3030–3034, 2001

    Google Scholar 

  68. Fuhrer DK, Feng GS, Yang YC: Syp associates with gp130 and Janus kinase 2 in response to interleukin-11 in 3T3-L1 mouse preadipocytes. J Biol Chem 270: 24826–24830, 1995

    Google Scholar 

  69. Barber DL, D'Andrea AD: Erythropoietin and interleukin-2 activate distinct JAK kinase family members. Mol Cell Biol 14: 6506–6514, 1994

    Google Scholar 

  70. Brizzi MF, Aronica MG, Rosso A, Bagnara GP, Yarden Y, Pegoraro L: Granulocyte-macrophage colony-stimulating factor stimulates JAK2 signaling pathway and rapidly activates p93fes, STAT1 p91, and STAT3 p92 in polymorphonuclear leukocytes. J Biol Chem 271: 3562–3567, 1996

    Google Scholar 

  71. Nicholson SE, Novak U, Ziegler SF, Layton JE: Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. Blood 86: 3698–3704, 1995

    Google Scholar 

  72. Ooi J, Tojo A, Asano S, Sato Y, Oka Y: Thrombopoietin induces tyrosine phosphorylation of a common beta subunit of GM-CSF receptor and its association with Stat5 in TF-1/TPO cells. Biochem Biophys Res Commun 246: 132–136, 1998

    Google Scholar 

  73. Silva CM, Lu H, Weber MJ, Thorner MO: Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon-gamma in IM-9 cells. J Biol Chem 269: 27532–27539, 1994

    Google Scholar 

  74. Buettner R, Mora LB, Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8: 945–954, 2002

    Google Scholar 

  75. Turkson J, Jove R: STAT proteins: Novel molecular targets for cancer drug discovery. Oncogene 19: 6613–6626, 2000

    Google Scholar 

  76. Mizuguchi R, Noto S, Yamada M, Ashizawa S, Higashi H, Hatakeyama M: Ras and signal transducer and activator of transcription (STAT) are essential and sufficient downstream components of Janus kinases in cell proliferation. Jap J Cancer Res 91: 527–533, 2000

    Google Scholar 

  77. Alam R, Pazdrak K, Stafford S, Forsythe P: The interleukin-5/receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras-Raf-1-MAP kinase and the Jak-STAT pathways in eosinophils. Int Arch All Immunol 107: 226–227, 1995

    Google Scholar 

  78. Kumar G, Gupta S, Wang S, Nel AE: Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth responsive B cell line. J Immunol 153: 4436–4447, 1994

    Google Scholar 

  79. Danial NN, Rothman P: JAK-STAT signaling activated by Abl oncogenes. Oncogene 9: 2523–2531, 2000

    Google Scholar 

  80. Wang JY, Ledley F, Goff S, Lee R, Groner Y, Baltimore D: The mouse c-abl locus: molecular cloning and characterization. Cell 36: 349–356, 1984

    Google Scholar 

  81. Kruh GD, King CR, Kraus MH, Popescu NC, Amsbaugh SC, McBride WO, Aaronson SA: A novel human gene closely related to the abl proto-oncogene. Science 234: 1545–1548, 1986

    Google Scholar 

  82. Chen YY, Wang LC, Huang MS, Rosenberg N: An active v-abl protein tyrosine kinase blocks immunoglobulin light-chain gene rearrangement. Gen Dev 8: 688–697, 1994

    Google Scholar 

  83. Danial NN, Losman JA, Lu T, Yip N, Krishnan K, Krolewski J, Goff SP, Wang JY, Rothman PB: Direct interaction of Jak1 and v-Abl is required for v-Ablinduced activation of STATs and proliferation. Mol Cell Biol 18: 6795–6804, 1998

    Google Scholar 

  84. Packham G, White EL, Eischen CM, Yang H, Parganas E, Ihle JN, Grillot DA, Zambetti GP, Nunez G, Cleveland JL: Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Gen Dev 12: 2475–2487, 1998

    Google Scholar 

  85. Sakai I, Kraft AS: The kinase domain of Jak2 mediates induction of bcl-2 and delays cell death in hematopoietic cells. J Biol Chem 272: 12350–12358, 1997

    Google Scholar 

  86. Wen R, Wang D, McKay C, Bunting KD, Marine JC, Vanin EF, Zambetti GP, Korsmeyer SJ, Ihle JN, Cleveland J: Jak3 selectively regulates Bax and BCl-2 expression to promote T-cell development. Mol Cell Biol 21: 678–689, 2001

    Google Scholar 

  87. Quelle FW, Wang J, Feng J, Wang D, Cleveland JL, Ihle JN, Zambetti GP: Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways. Gen Development 2: 1099–1107, 1998

    Google Scholar 

  88. Ward AC, Touw I, Yoshimura A: The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 95: 19–29, 2000

    Google Scholar 

  89. Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA: A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278: 1309–1312, 1997

    Google Scholar 

  90. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P: 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, 1997

    Google Scholar 

  91. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R Jr, Marynen P, Gilliland DG: Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo-and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 7: 5321–5333, 1998

    Google Scholar 

  92. Ho JM, Beattie BK, Squire JA, Frank DA, Barber DL: Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Blood 93: 4354–4364, 1999

    Google Scholar 

  93. Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee CK, Gerthner R, Kitamura T, Franstve J, Anastasiadou E, Loh ML, Levy DE, Ihle JN, Gilliland DG: Stat5 is essential for the myelo-and lymphoproliferative disease induced by Tel/Jak2. Mol Cell 6: 693–704, 2000

    Google Scholar 

  94. Harrison DA, Binari R, Nahreini TS, Gilman M, Perrimon N: Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J 14: 2857–2865, 1995

    Google Scholar 

  95. Luo H, Rose P, Barber D, Hanratty WP, Lee S, Roberts TM, D'Andrea AD, Dearolf CR: Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol Cell Biol 17: 1562–1571, 1997

    Google Scholar 

  96. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM: Inhibition of acute lymphoblastic leukaemia by a Jak2 inhibitor. Nature 379: 645–648, 1996

    Google Scholar 

  97. Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, Li Y, Wang JM, Yang-Yen HF, Karras J, Jove R, Loughran TP Jr: Inhibition of Stat3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107: 351–362, 2001

    Google Scholar 

  98. Ilaria RL Jr, Van Etten RA: P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. Journal of Biological Chemistry 271: 31704–31710, 1996

    Google Scholar 

  99. Kube D, Holtick U, Vockerodt M, Ahmadi T, Haier B, Behrmann I, Heinrich PC, Diehl V, Tesch H: STAT3 is constitutively activated in Hodgkin cell lines. Blood 98: 762–770, 2001

    Google Scholar 

  100. Nepomuceno RR, Snow AL, Robert Beatty P, Krams SM, Martinez OM: Constitutive activation of Jak/STAT proteins in Epstein Barr virus-infected B-cell lines from patients with posttransplant lymphoproliferative disorder. Transplantation 74: 396–402, 2002

    Google Scholar 

  101. Takemoto S, Mulloy JC, Cereseto A, Migone TS, Patel BK, Matsuoka M, Yamaguchi K, Takatsuki K, Kamihira S, White JD, Leonard WJ, Waldmann T, Franchini G: Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive acrivation of Jak/Stat proteins. Proc Natl Acad Sci USA 94: 13897–13902, 1997

    Google Scholar 

  102. Yu CL, Jove R, Burakoff SJ: Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lcktyrosine kinase. J Immunol 159: 5206–5210, 1997

    Google Scholar 

  103. Nielsen M, Kaltoft K, Nordahl M, Ropke C, Geisler C, Mustelin T, Dobson P, Svejgaard A, Odum N: Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines. Proc Natl Acad Sci USA 94: 6764–6769, 1997

    Google Scholar 

  104. Zhang Q, Nowak I, Vonderheid EC, Rook AH, Kadin ME, Nowell PC, Shaw LM, Wasik MA: Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large Tcell lymphoma and Sezary syndrome. Proc Nat Acad Sci USA 93: 9148–9153, 1996

    Google Scholar 

  105. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R: Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10: 105–115, 1999

    Google Scholar 

  106. Rawat R, Rainey GJ, Thompson CD, Frazier-Jessen MR, Brown RT, Nordan RP: Constitutive activation of Stat3 is associated with the acquisition of an interleukein 6-independent phenotype by murine plasmacytomas and hybridomas. Blood 96: 3514–3521, 2000

    Google Scholar 

  107. Oshiro MM, Landowski TH, Catlett-Falcone R, Hazlehurst LA, Huang M, Jove R, Dalton WS: Inhibition of Jak kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells. Clin Cancer Res 7: 4262–4271, 2001

    Google Scholar 

  108. De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B: Jak2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol 109: 823–828, 2000

    Google Scholar 

  109. Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R: Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Diff 8: 1267–1276, 1997

    Google Scholar 

  110. Sartor CI, Dziubinski ML, Yu CL, Jove R, Ethier SP: Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res 57: 978–987, 1997

    Google Scholar 

  111. Watson CJ, Miller WR: Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br J Cancer 71: 840–844, 1995

    Google Scholar 

  112. Xie W, Su K, Wang D, Paterson AJ, Kudlow JE: MDA468 growth inhibition by EGF is associated with the induction of the cyclin-dependent kinase inhibitor p21WAF1. Anticancer Res 17: 2627–2633, 1997

    Google Scholar 

  113. Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R, Yu H: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21: 7001–7010, 2002

    Google Scholar 

  114. Dhir R, Ni Z, Lou W, DeMiguel F, Grandis JR, Gao AC: Stat3 activation in prostatic carcinomas. Prostate 51: 241–246, 2002

    Google Scholar 

  115. Ni Z, Lou W, Leman ES, Gao AC: Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res 60: 1225–1228, 2000

    Google Scholar 

  116. Gao B, Shen X, Kunos G, Meng Q, Goldberg ID, Rosen EM, Fan S: Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. FEBS Letters 488: 179–184, 2001

    Google Scholar 

  117. Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD: Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA 97: 4227–4232, 2000

    Google Scholar 

  118. Song JI, Grandis JR: STAT signaling in head and neck cancer. Oncogene 19: 2489–2495, 2000

    Google Scholar 

  119. Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, Tomita K, Komiyama S, Weinstein IB: Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 62: 3351–3355, 2002

    Google Scholar 

  120. Kijima T, Niwa H, Steinman RA, Drenning SD, Gooding WE, Wentzel AL, Xi S, Grandis JR: STAT3 activation abrogates growth factor dependence and contributes to head and necksquamous cell carcinoma tumor growth in vitro. Cell Growth Differ 13: 355–362, 2002

    Google Scholar 

  121. Nagpal JK, Mishra R, Das BR: Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer 94: 2393–2400, 2000

    Google Scholar 

  122. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 44: 1038–1042, 2001

    Google Scholar 

  123. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031–1037, 2001

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center and Section of Hematology-Oncology, Northwestern University Medical School, Chicago, IL, USA

    Amit Verma, Suman Kambhampati, Simrit Parmar & Leonidas C. Platanias

Authors
  1. Amit Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suman Kambhampati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simrit Parmar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonidas C. Platanias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonidas C. Platanias.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verma, A., Kambhampati, S., Parmar, S. et al. Jak family of kinases in cancer. Cancer Metastasis Rev 22, 423–434 (2003). https://doi.org/10.1023/A:1023805715476

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1023805715476

Search

Navigation