Skip to main content
SpringerLink
Log in
Book cover

STAT Inhibitors in Cancer pp 1–32Cite as

STATs in Health and Disease

  • Chapter
  • First Online:

  • 592 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Signal Transducers and Activators of Transcription (STATs) represent a central paradigm of cell-cell signaling, providing a rapid and effective mechanism to transfer an external signal into a transcriptional response. They act as core components downstream of a myriad of cytokine and other receptors to mediate a diverse range of functions. This chapter provides an overview of the STAT protein family, their structure, mode of activation, specificity, variants and negative regulation along with their multiple roles in both normal biology as well as the etiology of disease.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36:503–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. O’Sullivan LA, Liongue C, Lewis RS et al (2007) Cytokine receptor signaling through the Jak/Stat/Socs pathway in disease. Mol Immunol 44:2497–2506

    Article  PubMed  CAS  Google Scholar 

  3. Kisseleva T, Bhattacharya S, Schroeder-Braunstein J et al (2002) Signaling through the JAK-STAT pathway: recent advances and future challenges. Gene 285:1–24

    Article  CAS  PubMed  Google Scholar 

  4. Neculai D, Neculai AM, Verrier S et al (2005) Structure of the unphosphorylated Stat5a dimer. J Biol Chem 280:40782–40787

    Article  CAS  PubMed  Google Scholar 

  5. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059–20063

    Article  CAS  PubMed  Google Scholar 

  6. Bromberg JF (2001) Activation of STAT proteins and growth control. Bioessays 23:161–169

    Article  CAS  PubMed  Google Scholar 

  7. Darnell JE Jr, Kerr IM, Stark GR (1994) JAK-STAT pathways and transcriptional activation in response to interferons and other extracellular signalling proteins. Science 264:1415–1421

    Article  CAS  PubMed  Google Scholar 

  8. Horvath CM, Darnell JE Jr (1997) The state of the STATs: recent developments in the study of signal transduction to the nucleus. Curr Opin Cell Biol 9:233–239

    Article  CAS  PubMed  Google Scholar 

  9. Heim MH, Kerr IM, Stark GR et al (1995) Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 267:1347–1349

    Article  CAS  PubMed  Google Scholar 

  10. Stahl N, Farruggella TJ, Bolton TG et al (1995) Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 267:1349–1353

    Article  CAS  PubMed  Google Scholar 

  11. Grandis JR, Drenning SD, Chakraborty A et al (1998) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth in vitro. J Clin Invest 102:1385–1392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Alonzi T, Maritano D, Gorgoni B et al (2001) Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation in the liver. Mol Cell Biol 21:1621–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Floss DM, Mrotzek S, Klocker T et al (2013) Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. J Biol Chem 288:19386–19400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chakraborty A, Dyer KF, Cascio M et al (1999) Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor. Blood 93:15–24

    CAS  PubMed  Google Scholar 

  15. Klingmuller U, Bergelson S, Hsiao JG et al (1996) Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proc Natl Acad Sci USA 93:8324–8328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Osborne LC, Duthie KA, Seo JH et al (2010) Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development. Oncogene 29:3854–3864

    Article  CAS  PubMed  Google Scholar 

  17. Hou J, Schindler U, Henzel WJ et al (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701–1706

    Article  CAS  PubMed  Google Scholar 

  18. Yan H, Krishnan K, Greenlund AC et al (1996) Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. EMBO J 15:1064–1074

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang YD, Wong K, Wood WI (1995) Intracellular tyrosine residues of the human growth hormone receptor are not required for the signaling of proliferation or Jak-STAT activation. J Biol Chem 270:7021–7024

    Article  CAS  PubMed  Google Scholar 

  20. Ward AC, Hermans MHA, Smith L et al (1999) Tyrosine-dependent and independent mechanisms of STAT3 activation by the human granulocyte colony-stimulating factor (G-CSF) receptor are differentially utilized depending on G-CSF concentration. Blood 93:113–124

    CAS  PubMed  Google Scholar 

  21. Mui AL-F, Wakao H, O’Farrell A-M et al (1995) Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J 14:1166–1175

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dong F, Liu X, de Koning JP et al (1998) Stimulation of Stat5 by granulocyte colony-stimulating factor (G-CSF) is modulated by two distinct cytoplasmic regions of the G-CSF receptor. J Immunol 161:6503–6509

    CAS  PubMed  Google Scholar 

  23. Barahmand-Pour F, Meinke A, Groner B et al (1998) Jak2-Stat5 interactions analyzed in yeast. J Biol Chem 273:12567–12575

    Article  CAS  PubMed  Google Scholar 

  24. Ali MS, Sayeski PP, Bernstein KE (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

    Article  CAS  PubMed  Google Scholar 

  25. Cao X, Tay A, Guy GR et al (1996) Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol 16:1595–1603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Caldenhoven E, Buitenhuis M, van Dijk TB et al (1999) Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils. J Leukoc Biol 65:391–396

    CAS  PubMed  Google Scholar 

  27. Caldenhoven E, van Dijk TB, Raaijmakers JAM et al (1999) Activation of a functionally distinct 80-kDa STAT5 isoform by IL-5 and GM-CSF in human eosinophils and neutrophils. Mol Cell Biol Res Commun 1:95–101

    Article  CAS  PubMed  Google Scholar 

  28. Castro A, Sengupta TK, Ruiz DC et al (1999) IL-4 selectively inhibits IL-2-triggered Stat5 activation, but not proliferation, in human T cells. J Immunol 162:1261–1269

    CAS  PubMed  Google Scholar 

  29. Ito S, Ansari P, Sakatsume M et al (1999) Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93:1456–1463

    CAS  PubMed  Google Scholar 

  30. Kolenko V, Rayman P, Roy B et al (1999) Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. Blood 93:2308–2318

    CAS  PubMed  Google Scholar 

  31. Lamb P, Seidel HM, Haslam J et al (1995) STAT protein complexes activated by interferon-γ and gp130 signaling molecules differ in their sequence preferences and transcriptional induction properties. Nucleic Acids Res 23:3283–3289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Seidel HM, Milocco LH, Lamb P et al (1995) Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc Natl Acad Sci USA 92:3041–3045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Basham B, Sathe M, Grein J et al (2008) In vivo identification of novel STAT5 target genes. Nucleic Acids Res 36:3802–3818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Decker T, Kovarik P, Meinke A (1997) GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17:121–134

    Article  CAS  PubMed  Google Scholar 

  35. Qureshi SA, Salditt-Georgieff M, Darnell JE Jr (1995) Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3. Proc Natl Acad Sci USA 92:3829–3833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bunting KD, Bradley HL, Hawley TS et al (2002) Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood 99:479–487

    Article  CAS  PubMed  Google Scholar 

  37. Zhang JJ, Zhao Y, Chait BT et al (1998) Ser727-dependent recruitment of MCM5 by Stat1α in IFN-γ-induced transcriptional activation. EMBO J 17:6963–6971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang JJ, Vinkemeier U, Gu W et al (1996) Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. Proc Natl Acad Sci USA 93:15092–15096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Look DC, Pelletier MR, Tidwell RM et al (1995) Stat1 depends on transcriptional synergy with Sp1. J Biol Chem 270:30264–30267

    Article  CAS  PubMed  Google Scholar 

  40. Zhang X, Wrzeszczynska MH, Horvath CM et al (1999) Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation. Mol Cell Biol 19:7138–7146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wyszomierski SL, Rosen JM (2001) Cooperative effects of STAT5 (signal transducer and activator of transcription 5) and C/EBPbeta (CCAAT/enhancer-binding protein-beta) on beta-casein gene transcription are mediated by the glucocorticoid receptor. Mol Endocrinol 15:228–240

    CAS  PubMed  Google Scholar 

  42. Zhu M-h, John S, Berg M et al (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNγ-mediated signaling. Cell 96:121–130

    Article  CAS  PubMed  Google Scholar 

  43. Mui AL-F, Wakao H, Kinoshita T et al (1996) Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J 15:2425–2433

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Moriggl R, Gouilleux-Gruart V, Jahne R et al (1996) Deletion of the carboxyl terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol 16:6141–6148

    Article  Google Scholar 

  45. Caldenhoven E, van Dijk TB, Solari R et al (1996) STAT3 beta, a splice variant of transcription factor STAT3, is a dominant-negative regulator of transcription. J Biol Chem 271:13221–13227

    CAS  PubMed  Google Scholar 

  46. de Koning JP, Ward AC, Caldenhoven E et al (2000) STAT3beta does not interfere with granulocyte colony-stimulating factor-induced neutrophilic differentiation. Hematol J 1:220–225

    Article  PubMed  Google Scholar 

  47. Hoey T, Zhang S, Schmidt N et al (2003) Distinct requirements for the naturally occurring splice forms Stat4α and Stat4β in IL-12 responses. EMBO J 22:4237–4248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sherman MA (2001) The role of STAT6 in mast cell IL-4 production. Immunol Rev 179:48–56

    Article  CAS  PubMed  Google Scholar 

  49. Chakraborty A, Tweardy DJ (1998) Granulocyte colony-stimulating factor activates a 72-kDa isoform of STAT3 in human neutrophils. J Leukoc Biol 64:675–680

    CAS  PubMed  Google Scholar 

  50. Hevehan DL, Miller WM, Papoutsakis ET (2002) Differential expression and phosphorylation of distinct STAT3 proteins during granulocytic differentiation. Blood 99:1627–1637

    Article  CAS  PubMed  Google Scholar 

  51. Chakraborty A, Dyer KF, Tweardy DJ (2000) Delineation and mapping of Stat5 isoforms activated by granulocyte colony-stimulating factor in myeloid cells. Blood Cells Mol Dis 26:320–330

    Article  CAS  PubMed  Google Scholar 

  52. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635

    Article  CAS  PubMed  Google Scholar 

  53. de Koning JP, Dong F, Smith L et al (1996) The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood 87:1335–1342

    PubMed  Google Scholar 

  54. Ward AC, van Aesch YM, Schelen AM et al (1999) Defective internalization and sustained activation of truncated granulocyte colony-stimulating factor receptor found in severe congenital neutropenia/acute myeloid leukemia. Blood 93:447–458

    CAS  PubMed  Google Scholar 

  55. Collison LW, Delgoffe GM, Guy CS et al (2012) The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol 13:290–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Trinchieri G, Pflanz S, Kastelein RA (2003) The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19:641–644

    Article  CAS  PubMed  Google Scholar 

  57. Zhang X, Blenis J, Li H-C et al (1995) Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 267:1990–1994

    Article  CAS  PubMed  Google Scholar 

  58. Wen Z, Zhong Z, Darnell JE Jr (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250

    Article  CAS  PubMed  Google Scholar 

  59. Jain N, Zhang T, Fong SL et al (1998) Repression of Stat3 activity by activation of mitogen-activated protein kinase. Oncogene 17:3157–3167

    Article  CAS  PubMed  Google Scholar 

  60. Tenoever BR, Ng SL, Chua MA et al (2007) Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science 315:1274–1278

    Article  CAS  PubMed  Google Scholar 

  61. Ng SL, Friedman BA, Schmid S et al (2011) IkappaB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses. Proc Natl Acad Sci U S A 108:21170–21175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang J, Huang J, Dasgupta M et al (2010) Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci USA 107:21499–21504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yuan ZL, Guan YJ, Chatterjee D et al (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307:269–273

    Article  CAS  PubMed  Google Scholar 

  64. Ungureanu D, Vanhatupa S, Gronholm J et al (2005) SUMO-1 conjugation selectively modulates STAT1-mediated gene responses. Blood 106:224–226

    Article  CAS  PubMed  Google Scholar 

  65. Ungureanu D, Silvennoinen O (2005) SLIM trims STATs: ubiquitin E3 ligases provide insights for specificity in the regulation of cytokine signaling. Sci STKE 304:pe9

    Google Scholar 

  66. Ray S, Zhao Y, Jamaluddin M et al (2014) Inducible STAT3 NH2 terminal mono-ubiquitination promotes BRD4 complex formation to regulate apoptosis. Cell Signal 26:1445–1455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Iwasaki H, Kovacic JC, Olive M et al (2010) Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation. Circ Res 107:992–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Droescher M, Begitt A, Marg A et al (2011) Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). J Biol Chem 286:18731–18746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nie Y, Erion DM, Yuan Z et al (2009) STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat Cell Biol 11:492–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sestito R, Madonna S, Scarponi C et al (2011) STAT3-dependent effects of IL-22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation. FASEB J 25:916–927

    Article  CAS  PubMed  Google Scholar 

  71. Zhang X, Guo A, Yu J et al (2007) Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci USA 104:4060–4064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Andersen JN, Mortensen OH, Peters GH et al (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21:7117–7136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Poole AW, Jones ML (2005) A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal 17:1323–1332

    Article  CAS  PubMed  Google Scholar 

  74. ten Hoeve J, de Jesus I-SM, Fu Y et al (2002) Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 22:5662–5668

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Woetmann A, Nielsen M, Christensen ST et al (1999) Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3. Proc Natl Acad Sci USA 96:10620–10625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824

    Article  CAS  PubMed  Google Scholar 

  77. Trengove MC, Ward AC (2013) SOCS proteins in development and disease. Am J Exp Clin Immunol 2:1–29

    Google Scholar 

  78. Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593–605

    Article  CAS  PubMed  Google Scholar 

  79. Palvimo JJ (2007) PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription. Biochem Soc Trans 35:1405–1408

    Article  CAS  PubMed  Google Scholar 

  80. Lin G, LaPensee CR, Qin ZS et al (2014) Reciprocal occupancy of BCL6 and STAT5 on Growth Hormone target genes: contrasting transcriptional outcomes and promoter-specific roles of p300 and HDAC3. Mol Cell Endocrinol 395:19–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Neel BG, Gu H, Pao L (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28:284–293

    Article  CAS  PubMed  Google Scholar 

  82. Neel BG, Tonks NK (1997) Protein tyrsosine phosphatases in signal transduction. Curr Opin Cell Biol 9:193–204

    Article  CAS  PubMed  Google Scholar 

  83. Yoshimura A, Ohkubo T, Kiguchi T et al (1995) A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 14:2816–2826

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Klingmuller U, Lorenz U, Cantley LC et al (1995) Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80:729–739

    Article  CAS  PubMed  Google Scholar 

  85. Chen Y, Wen R, Yang S et al (2003) Identification of Shp-2 as a Stat5A phosphatase. J Biol Chem 278:16520–16527

    Article  CAS  PubMed  Google Scholar 

  86. Nicholson SE, De Souza D, Fabri LJ et al (2000) Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci USA 97:6493–6498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Esashi E, Wang YH, Perng O et al (2008) The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28:509–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mandal M, Powers SE, Maienschein-Cline M et al (2011) Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat Immunol 12:1212–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen H, Sun H, You F et al (2011) Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147:436–446

    Article  CAS  PubMed  Google Scholar 

  90. Gao X, Wang H, Yang JJ et al (2012) Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell 45:598–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee JE, Yang YM, Liang FX et al (2012) Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol 302:C804–C820

    Article  CAS  PubMed  Google Scholar 

  92. Christova R, Jones T, Wu PJ et al (2007) P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNgamma. J Cell Sci 120:3262–3270

    Article  CAS  PubMed  Google Scholar 

  93. Yang J, Chatterjee-Kishore M, Staugaitis SM et al (2005) Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 65:939–947

    CAS  PubMed  Google Scholar 

  94. Yang J, Liao X, Agarwal MK et al (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 21:1396–1408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Morrow AN, Schmeisser H, Tsuno T et al (2011) A novel role for IFN-stimulated gene factor 3II in IFN-gamma signaling and induction of antiviral activity in human cells. J Immunol 186:1685–16893

    Article  CAS  PubMed  Google Scholar 

  96. Park HJ, Li J, Hannah R et al (2016) Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program. EMBO J 35(6):580–594

    Article  CAS  PubMed  Google Scholar 

  97. Cheon H, Yang J, Stark GR (2011) The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins. J Interferon Cytokine Res 31:33–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yan SJ, Lim SJ, Shi S et al (2011) Unphosphorylated STAT and heterochromatin protect genome stability. FASEB J 25:232–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shuai K, Schindler C, Prezioso VR et al (1992) Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science 258:1808–1812

    Article  CAS  PubMed  Google Scholar 

  100. Shuai K, Stark GR, Kerr IM et al (1993) A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science 261:1744–1746

    Article  CAS  PubMed  Google Scholar 

  101. Kotenko SV, Gallagher G, Baurin VV et al (2003) IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4:69–77

    Article  CAS  PubMed  Google Scholar 

  102. Shuai K, Ziemiecki A, Wilks AF et al (1993) Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 366:580–583

    Article  CAS  PubMed  Google Scholar 

  103. Nicholson SE, Novak U, Ziegler SF et al (1995) Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44 MAPK. Blood 86:3698–3704

    CAS  PubMed  Google Scholar 

  104. Freeth JS, Silva CM, Whatmore AJ et al (1998) Activation of the signal transducers and activators of transcription signaling pathway by growth hormone (GH) in skin fibroblasts from normal and GH binding protein-positive Laron syndrome children. Endocrinology 139:20–28

    Article  CAS  PubMed  Google Scholar 

  105. Sahni M, Ambrosetti DC, Mansukhani A et al (1999) FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev 13:1361–1366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wong M, Uddin S, Majchrzak B et al (2001) Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. J Biol Chem 276:11427–11431

    Article  CAS  PubMed  Google Scholar 

  107. Durbin JE, Hackenmiller R, Simon MC et al (1996) Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 85:443–450

    Article  Google Scholar 

  108. Meraz MA, White JM, Sheehan KCF et al (1996) Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431–442

    Article  CAS  PubMed  Google Scholar 

  109. Dickensheets H, Sheikh F, Park O et al (2013) Interferon-lambda (IFN-lambda) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes. J Leukoc Biol 93:377–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kaplan DH, Shankaran V, Dighe AS et al (1998) Demonstration of an interferon gamma-dependent tumor surveillence system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556–7561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kernbauer E, Maier V, Stoiber D et al (2012) Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. PLoS Pathog 8:e1002763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Johnson LM, Scott P (2007) STAT1 expression in dendritic cells, but not T cells, is required for immunity to Leishmania major. J Immunol 178:7259–7266

    Article  CAS  PubMed  Google Scholar 

  113. Schindler C, Fu XY, Improta T et al (1992) Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci USA 89:7836–7839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Park C, Li S, Cha E et al (2000) Immune response in Stat2 knockout mice. Immunity 13:795–804

    Article  CAS  PubMed  Google Scholar 

  115. Perry ST, Buck MD, Lada SM et al (2011) STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS Pathog 7:e1001297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98

    Article  CAS  PubMed  Google Scholar 

  117. Akira S, Nishio Y, Inoue M et al (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signalling pathway. Cell 77:63–71

    Article  CAS  PubMed  Google Scholar 

  118. Heinrich PC, Behrmann I, Muller-Newen G et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Donnelly RP, Dickensheets H, Finbloom DS (1999) The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res 19:563–573

    Article  CAS  PubMed  Google Scholar 

  120. Park ES, Kim H, Suh JM et al (2000) Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway. Mol Endocrinol 14:662–670

    Article  CAS  PubMed  Google Scholar 

  121. Yanagisawa M, Nakashima K, Arakawa H et al (2000) Astrocyte differentiation of fetal neuroepithelial cells by interleukin-11 via activation of a common cytokine signal transducer, gp130, and a transcription factor, STAT3. J Neurochem 74:1498–1504

    Article  CAS  PubMed  Google Scholar 

  122. Bowman T, Broome MA, Sinibaldi D et al (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci USA 98:7319–7324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Bartoli M, Platt D, Lemtalsi T et al (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17:1562–1564

    CAS  PubMed  Google Scholar 

  124. Arredondo J, Chernyavsky AI, Jolkovsky DL et al (2006) Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes. FASEB J 20:2093–2101

    Article  CAS  PubMed  Google Scholar 

  125. Landen CN Jr, Lin YG, Armaiz Pena GN et al (2007) Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer. Cancer Res 67:10389–10396

    Article  CAS  PubMed  Google Scholar 

  126. Caprioli F, Sarra M, Caruso R et al (2008) Autocrine regulation of IL-21 production in human T lymphocytes. J Immunol 180:1800–1807

    Article  CAS  PubMed  Google Scholar 

  127. Kortylewski M, Kujawski M, Herrmann A et al (2009) Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res 69:2497–2505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sonnenberg GF, Fouser LA, Artis D (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 12:383–390

    Article  CAS  PubMed  Google Scholar 

  129. Takeda K, Tanaka T, Shi W et al (1996) Essential role of Stat6 in IL-4 signalling. Nature 380:627–630

    Article  CAS  PubMed  Google Scholar 

  130. Takeda K, Kaisho T, Yoshida N et al (1998) Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 161:4652–4660

    CAS  PubMed  Google Scholar 

  131. Yang XO, Panopoulos AD, Nurieva R et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    Article  CAS  PubMed  Google Scholar 

  132. Chaudhry A, Rudra D, Treuting P et al (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326:986–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Takeda K, Clausen BE, Kaisho T et al (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–49

    Article  CAS  PubMed  Google Scholar 

  134. Jacoby JJ, Kalinowski A, Liu MG et al (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A 100:12929–12934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sano S, Itami S, Takeda K et al (1999) Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 18:4657–4668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Alonzi T, Middleton G, Wyatt S et al (2001) Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons. Mol Cell Neurosci 18:270–282

    Article  CAS  PubMed  Google Scholar 

  137. Chapman RS, Lourenco PC, Tonner E et al (1999) Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 13:2604–2616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sano S, Takahama Y, Sugawara T et al (2001) Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 15:261–273

    Article  CAS  PubMed  Google Scholar 

  139. Jacobson NG, Szabo SJ, Weber-Nordt RM et al (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 181:1755–1762

    Article  CAS  PubMed  Google Scholar 

  140. Kaplan MH, Sun YL, Hoey T et al (1996) Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382:174–177

    Article  CAS  PubMed  Google Scholar 

  141. Azam M, Erdjument-Bromage H, Kreider BL et al (1995) Interleukin-3 signals through multiple isoforms of Stat5. EMBO J 14:1402–1411

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Gouilleux F, Wakao H, Mundt M et al (1994) Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J 13:4361–4369

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Liu X, Robinson GW, Gouilleux F et al (1995) Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc Natl Acad Sci U S A 92:8831–8835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pallard C, Gouilleux F, Benit L et al (1995) Thrombopoietin activates a STAT5-like factor in hematopoietic cells. EMBO J 14:2847–2856

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Demoulin JB, Uyttenhove C, Van Roost E et al (1996) A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol Cell Biol 16:4710–4716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tian S-S, Tapley P, Sincich C et al (1996) Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. Blood 88:4435–4444

    CAS  PubMed  Google Scholar 

  147. Novak U, Mui A, Miyajima A et al (1996) Formation of STAT5-containing DNA binding complexes in response to colony-stimulating factor-1 and platelet-derived growth factor. J Biol Chem 271:18350–18354

    Article  CAS  PubMed  Google Scholar 

  148. Valgeirsdottir S, Paukku K, Silvennoinen O et al (1998) Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains. Oncogene 16:505–515

    Article  CAS  PubMed  Google Scholar 

  149. Lin JX, Leonard WJ (2000) The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19:2566–2576

    Article  CAS  PubMed  Google Scholar 

  150. Liu X, Robinson GW, Wagner K-U et al (1997) Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 11:179–186

    Article  CAS  PubMed  Google Scholar 

  151. Nakajima H, Liu XW, Wynshaw-Boris A et al (1997) An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. Immunity 7:691–701

    Article  CAS  PubMed  Google Scholar 

  152. Udy GB, Towers RP, Snell RG et al (1997) Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 94:7239–7244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Imada K, Bloom ET, Nakajima H et al (1998) Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J Exp Med 188:2067–2074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Teglund S, McKay C, Schuetz E et al (1998) Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841–850

    Article  CAS  PubMed  Google Scholar 

  155. Socolovasky M, Fallon AEJ, Wang S et al (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-XL induction. Cell 98:181–191

    Article  Google Scholar 

  156. Moriggl R, Topham DJ, Teglund S et al (1999) Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:249–259

    Article  CAS  PubMed  Google Scholar 

  157. Sexl V, Piekorz R, Moriggl R et al (2000) Stat5a/b contribute to interleukin 7-induced B-cell precursor expansion, but ABL- and BCR/ABL-induced transformation are independent of Stat5. Blood 96:2277–2283

    CAS  PubMed  Google Scholar 

  158. Yao Z, Cui Y, Watford WT et al (2006) Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA 104:1000–1004

    Article  CAS  Google Scholar 

  159. Hoelbl A, Kovavic B, Kerenyi MA et al (2006) Clarifying the role of Stat5 in lymphoid development and Abelson induced transformation. Blood 107:4898–4906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Laurence A, Tato CM, Davidson TS et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    Article  CAS  PubMed  Google Scholar 

  161. Johnston RJ, Choi YS, Diamond JA et al (2012) STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med 209:243–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhu BM, McLaughlin SK, Na R et al (2008) Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression. Blood 112(5):2071–2080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kimura A, Rieger MA, Simone JM et al (2009) The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis. Blood 114:4721–4728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Cui Y, Riedlinger G, Miyoshi K et al (2004) Inactivation of Stat5 in mouse mammary epithelial during pregancy reveals distinct functions in cell proliferation, survival and differentiation. Mol Cell Biol 24:8037–8047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Engblom D, Kornfeld JW, Schwake L et al (2007) Direct glucocorticoid receptor-Stat5 interaction in hepatocytes control body size and maturation-related gene expression. Genes Dev 21:1157–1162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cui Y, Hosui A, Sun R et al (2007) Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology 46:504–513

    Article  CAS  PubMed  Google Scholar 

  167. Holloway MG, Cui Y, Laz EV et al (2007) Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus. Endocrinology 148:1977–1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Klover P, Hennighausen L (2007) Postnatal body growth is dependent on the transcription factors signal transducers and activators of transcription 5a/b in muscle: a role for autocrine/paracrine insulin-like growth factor 1. Endocrinology 148:1489–1497

    Article  CAS  PubMed  Google Scholar 

  169. Lin J-X, Migone TS, Tsang M et al (1995) The role of shared receptor motifs and common STAT proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13 and IL-15. Immunity 2:331–339

    Article  CAS  PubMed  Google Scholar 

  170. Kaplan MH, Schindler U, Smiley ST et al (1996) Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity 4:313–319

    Article  CAS  PubMed  Google Scholar 

  171. O’Shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161–170

    Article  PubMed  CAS  Google Scholar 

  172. Dupuis S, Dargemont C, Fieschi C et al (2001) Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293:300–303

    Article  CAS  PubMed  Google Scholar 

  173. Dupuis S, Jouanguy E, Al-Hajjar S et al (2003) Impaired response to interferon-gamma/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33:388–391

    Article  CAS  PubMed  Google Scholar 

  174. Sharfe N, Nahum A, Newell A et al (2014) Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol 133:807–817

    Article  CAS  PubMed  Google Scholar 

  175. Minegishi Y, Saito M, Tsuchiya S et al (2007) Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058–1062

    Article  CAS  PubMed  Google Scholar 

  176. Kofoed EM, Hwa V, Little B et al (2003) Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 349:1139–1147

    Article  CAS  PubMed  Google Scholar 

  177. Yao Z, Cui Y, Watford WT et al (2006) Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA 103(4):1000–1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Liongue C, Wright C, Russell AP et al (2009) Granulocyte colony-stimulating factor receptor: stimulating granulopoiesis and much more. Int J Biochem Cell Biol 41:2372–2375

    Article  CAS  PubMed  Google Scholar 

  179. Sampath D, Castro M, Look DC et al (1999) Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J Clin Invest 103:1353–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Liu L, Okada S, Kong XF et al (2011) Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 208:1635–1648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Sampaio EP, Hsu AP, Pechacek J et al (2013) Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol 131:1624–1634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jakkula E, Leppa V, Sulonen AM et al (2010) Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am J Hum Genet 86:285–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Remmers EF, Plenge RM, Lee AT et al (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357:977–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Lovato P, Brender C, Agnholt J et al (2003) Constitutive STAT3 activation in intestinal T cells from patients with Crohn’s disease. J Biol Chem 278:16777–16781

    Article  CAS  PubMed  Google Scholar 

  185. Di Stefano A, Caramori G, Capelli A et al (2004) STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Eur Respir J 24:78–85

    Article  PubMed  CAS  Google Scholar 

  186. Pertovaara M, Silvennoinen O, Isomaki P (2015) STAT-5 is activated constitutively in T cells, B cells and monocytes from patients with primary Sjogren’s syndrome. Clin Exp Immunol 181:29–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Murata K, Kumagai H, Kawashima T et al (2003) Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem 278:32892–32898

    Article  CAS  PubMed  Google Scholar 

  188. Andrejeva J, Young DF, Goodbourn S et al (2002) Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons. J Virol 76:2159–2167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Parisien JP, Lau JF, Horvath CM (2002) STAT2 acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus 5 replication. J Virol 76:6435–6441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Afroz S, Brownlie R, Fodje M et al (2016) VP8, the major tegument protein of bovine herpesvirus-1, interacts with cellular STAT1 and inhibits interferon-beta signaling. J Virol 90:4889–4904

    Google Scholar 

  191. Landires I, Bugault F, Lambotte O et al (2011) HIV infection perturbs interleukin-7 signaling at the step of STAT5 nuclear relocalization. AIDS 25:1843–1853

    Article  CAS  PubMed  Google Scholar 

  192. James C, Ugo V, Le Couédic J-P et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148

    Article  CAS  PubMed  Google Scholar 

  193. Shuai K, Halpern J, ten Hoeve J et al (1996) Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene 13:247–254

    CAS  PubMed  Google Scholar 

  194. Arcasoy MO, Harris KW, Forget BG (1999) A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation. Exp Hematol 27:63–74

    Article  CAS  PubMed  Google Scholar 

  195. Gibson SE, Schade AE, Szpurka H et al (2008) Phospho-STAT5 expression pattern with the MPL W515L mutation is similar to that seen in chronic myeloproliferative disorders with JAK2 V617F. Hum Pathol 39:1111–1114

    Article  CAS  PubMed  Google Scholar 

  196. de Groot RP, Raaijmakers JAM, Lammers J-WJ et al (1999) STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells. Blood 94:1108–1112

    PubMed  Google Scholar 

  197. Funakoshi-Tago M, Tago K, Abe M et al (2010) STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant. J Biol Chem 285:5296–5307

    Article  CAS  PubMed  Google Scholar 

  198. Bar-Natan M, Nelson EA, Walker SR et al (2012) Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells. Leukemia 26:1407–1410

    Article  CAS  PubMed  Google Scholar 

  199. Weber-Nordt RM, Egen C, Wehinger J et al (1996) Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood 88:809–816

    CAS  PubMed  Google Scholar 

  200. Gouilleux-Gruart B, Gouilleux F, Desaint C et al (1996) STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood 87:1692–1697

    CAS  PubMed  Google Scholar 

  201. Hayakawa F, Towatari M, Iida H et al (1998) Differential constitutive activation between STAT-related proteins and MAP kinase in primary acute myelogenous leukaemia. Br J Haematol 101:521–528

    Article  CAS  PubMed  Google Scholar 

  202. Catlett-Falcone R, Landowski TH, Oshiro MM et al (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105–115

    Article  CAS  PubMed  Google Scholar 

  203. Dolled-Filhart M, Camp RL, Kowalski DP et al (2003) Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. Clin Cancer Res 9:594–600

    CAS  PubMed  Google Scholar 

  204. Calo V, Migliavacca M, Bazan V et al (2003) STAT proteins: from normal control of cellular events to tumorigenesis. J Cell Physiol 197:157–168

    Article  CAS  PubMed  Google Scholar 

  205. Skinnider BF, Elia AJ, Gascoyne RD et al (2002) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99:618–626

    Article  CAS  PubMed  Google Scholar 

  206. Hornakova T, Staerk J, Royer Y et al (2009) Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. J Biol Chem 284:6773–6781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Lee JW, Kim YG, Soung YH et al (2006) The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 25:1434–1436

    Article  CAS  PubMed  Google Scholar 

  208. Yin C, Sandoval C, Baeg GH (2015) Identification of mutant alleles of JAK3 in pediatric patients with acute lymphoblastic leukemia. Leuk Lymphoma 56:1502–1506

    Article  CAS  PubMed  Google Scholar 

  209. Schwaller J, Parganas E, Wang D et al (2000) Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 6:693–704

    Article  CAS  PubMed  Google Scholar 

  210. Gale RE, Freeburn RW, Khwaja A et al (1998) A truncated isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 with increased mRNA expression in some patients with acute leukemia. Blood 91:54–63

    CAS  PubMed  Google Scholar 

  211. Testa U, Riccioni R, Diverio D et al (2004) Interleukin-3 receptor in acute leukemia. Leukemia 18:219–226

    Article  CAS  PubMed  Google Scholar 

  212. Gits J, van Leeuwen D, Carroll HP et al (2006) Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors. Leukemia 20:2111–2118

    Article  CAS  PubMed  Google Scholar 

  213. Scheeren FA, Diehl SA, Smit LA et al (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111:4706–4715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Klampfl T, Gisslinger H, Harutyunyan AS et al (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369:2379–2390

    Article  CAS  PubMed  Google Scholar 

  215. Kiel MJ, Sahasrabuddhe AA, Rolland DC et al (2015) Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat Commun 6:8470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Moriggl R, Sexl V, Kenner L et al (2005) Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell 7:87–99

    Article  CAS  PubMed  Google Scholar 

  217. Lewis RS, Stephenson SEM, Ward AC (2006) Constitutive activation of zebrafish stat5 expands hematopoietic cell populations in vivo. Exp Hematol 34:179–187

    Article  CAS  PubMed  Google Scholar 

  218. Grandis JR, Drenning SD, Zeng Q et al (2000) Constitutive activation of Stat3 signaling abbrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci U S A 97:4227–4232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Campbell CL, Jiang Z, Savarese DM et al (2001) Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. Am J Pathol 158:25–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Burke WM, Jin X, Lin HJ et al (2001) Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene 20:7925–7934

    Article  CAS  PubMed  Google Scholar 

  221. Baumgart S, Chen NM, Siveke JT et al (2014) Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 4:688–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Errico A (2015) Lung cancer: Driver-mutation-dependent stratification: learning from STAT3. Nat Rev Clin Oncol 12:251

    Article  PubMed  Google Scholar 

  223. Campbell CL, Guardiani R, Ollari C et al (2001) Interleukin-11 receptor expression in primary ovarian carcinomas. Gynecol Oncol 80:121–127

    Article  CAS  PubMed  Google Scholar 

  224. Reynolds C, Montone KT, Powell CM et al (1997) Expression of prolactin and its receptor in human breast carcinoma. Endocrinology 138:5555–5560

    CAS  PubMed  Google Scholar 

  225. Fan QW, Cheng CK, Gustafson WC et al (2013) EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 24:438–449

    Article  CAS  PubMed  Google Scholar 

  226. Bromberg JF, Horvath CM, Besser D et al (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553–2558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Xi S, Zhang Q, Dyer KF et al (2003) Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J Biol Chem 278:31574–31583

    Article  CAS  PubMed  Google Scholar 

  228. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Costa-Pereira AP, Bonito NA, Seckl MJ (2011) Dysregulation of janus kinases and signal transducers and activators of transcription in cancer. Am J Cancer Res 1:806–816

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Peyser ND, Du Y, Li H et al (2015) Loss-of-function PTPRD mutations lead to increased STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. PLoS One 10:e0135750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Frank DA (2003) STAT signaling in cancer: insights into pathogenesis and treatment strategies. Cancer Treat Res 115:267–291

    Article  CAS  PubMed  Google Scholar 

  232. Iavnilovitch E, Cardiff RD, Groner B et al (2004) Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. Int J Cancer 112:607–619

    Article  CAS  PubMed  Google Scholar 

  233. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Mascareno E, El-Shafei M, Maulik N et al (2001) JAK/STAT signaling is associated with cardiac dysfunction during ischemia and reperfusion. Circulation 104:325–329

    Article  CAS  PubMed  Google Scholar 

  235. Kiuchi N, Nakajima K, Ichiba M et al (1999) STAT3 is required for the gp130-mediated full activation of the c-myc gene. J Exp Med 189:63–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Nosaka T, Kawashima T, Misawa K et al (1999) STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J 18:4754–4765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Shirogane T, Fukada T, Muller JM et al (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11:709–719

    Article  CAS  PubMed  Google Scholar 

  238. Ouyang W, Ranganath S, Weindel K et al (1998) Inhibition of Th1 development mediated by GATA-3 through an IL-4 independent mechanism. Immunity 9:745–755

    Article  CAS  PubMed  Google Scholar 

  239. Matsumura I, Kitamura T, Wakao H et al (1999) Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells. EMBO J 18:1367–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Sakamoto K, Creamer BA, Triplett AA et al (2007) The Janus kinase 2 is required for expression and nuclear accumulation of cyclin D1 in proliferating mammary epithelial cells. Mol Endocrinol 21:1877–1892

    Article  CAS  PubMed  Google Scholar 

  241. Harris J, Stanford PM, Sutherland KD et al (2006) Socs2 and Elf5 mediate prolactin-induced mammary gland development. Mol Endocrinol 20:1177–1187

    Article  CAS  PubMed  Google Scholar 

  242. Walker SR, Nelson EA, Frank DA (2007) STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26:224–233

    Article  CAS  PubMed  Google Scholar 

  243. Olson MR, Verdan FF, Hufford MM et al (2016) STAT3 impairs STAT5 activation in the development of IL-9-secreting T cells. J Immunol 196(8):3297–3304

    Article  CAS  PubMed  Google Scholar 

  244. Wooten DK, Xie X, Bartos D et al (2000) Cytokine signaling through Stat3 activates integrins, promotes adhesion, and induces growth arrest in the myeloid cell line 32D. J Biol Chem 275:26566–26575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Goenka S, Kaplan MH (2011) Transcriptional regulation by STAT6. Immunol Res 50:87–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Yamaji D, Kang K, Robinson GW et al (2013) Sequential activation of genetic programs in mouse mammary epithelium during pregnancy depends on STAT5A/B concentration. Nucleic Acids Res 41:1622–1636

    Article  CAS  PubMed  Google Scholar 

  247. Grad JM, Zeng XR, Boise LH (2000) Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol 12:543–549

    Article  CAS  PubMed  Google Scholar 

  248. Fukada T, Hibi M, Yamanaka Y et al (1996) Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5:449–460

    Article  CAS  PubMed  Google Scholar 

  249. Feldman GM, Rosenthal LA, Liu X et al (1997) STAT5A-deficient mice demonstrate a defect in granulocyte-macrophage colony-stimulating factor-induced proliferation and gene expression. Blood 90:1768–1776

    CAS  PubMed  Google Scholar 

  250. Dumon S, Santos SC, Debierre-Grockiego F et al (1999) IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line. Oncogene 18:4191–4199

    Article  CAS  PubMed  Google Scholar 

  251. Silva M, Benito A, Sanz C et al (1999) Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. J Biol Chem 274:22165–22169

    Article  CAS  PubMed  Google Scholar 

  252. Gritsko T, Williams A, Turkson J et al (2006) Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11–19

    Article  CAS  PubMed  Google Scholar 

  253. Creamer BA, Sakamoto K, Schmidt JW et al (2010) Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1. Mol Cell Biol 30:2957–2970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Zimmerman MA, Rahman NT, Yang D et al (2012) Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance. Cancer Res 72:4724–4732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Alexander WS, Starr R, Fenner JE et al (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608

    Article  CAS  PubMed  Google Scholar 

  256. Wang S, Raven JF, Durbin JE et al (2008) Stat1 phosphorylation determines Ras oncogenicity by regulating p27 kip1. PLoS One 3, e3476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. Lee CK, Smith E, Gimeno R et al (2000) STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol 164:1286–1292

    Article  CAS  PubMed  Google Scholar 

  258. de Koning JP, Soede-Bobok AA, Ward AC et al (2000) STAT3-mediated differentiation and survival of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27Kip1. Oncogene 19:3290–3298

    Article  PubMed  Google Scholar 

  259. Matsumura I, Ishikawa J, Nakajima K et al (1997) Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAF1/Cip1) by STAT5. Mol Cell Biol 17:2933–2943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Narimatsu M, Nakajima K, Ichiba M et al (1997) Association of Stat3-dependent transcriptional activation of p19INK4D with IL-6-induced growth arrest. Biochem Biophys Res Commun 238:764–768

    Article  CAS  PubMed  Google Scholar 

  261. Ramana CV, Grammatikakis N, Chernov M et al (2000) Regulation of c-Myc expression by IFN-gamma through Stat1-dependent and -independent pathways. EMBOJ 19:263–272

    Article  CAS  Google Scholar 

  262. Dimco G, Knight RA, Latchman DS et al (2010) STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest. Cell Cycle 9:4638–4649

    Article  CAS  PubMed  Google Scholar 

  263. Nakajima K, Yamanaka Y, Nakae K et al (1996) A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J 15:3651–3658

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Minami M, Inoue M, Wei S et al (1996) STAT3 activation is a critical step in GP130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci U S A 93:3963–3966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Rauch I, Muller M, Decker T (2013) The regulation of inflammation by interferons and their STATs. JAKSTAT 2:e23820

    PubMed  PubMed Central  Google Scholar 

  266. Han G, Zhao W, Wang L et al (2014) Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression. Brain Res 1543:1–8

    Article  CAS  PubMed  Google Scholar 

  267. Nakayamada S, Kanno Y, Takahashi H et al (2011) Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35:919–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Zorn E, Nelson EA, Mohseni M et al (2006) IL-2 regulates FOXP3 expression in human CD4 + CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108:1571–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Maier E, Duschl A, Horejs-Hoeck J (2012) STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol 42:2827–2833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Kapoor N, Niu J, Saad Y et al (2015) Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. J Immunol 194:6011–6023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Niu G, Wright KL, Huang M et al (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008

    Article  CAS  PubMed  Google Scholar 

  272. Devarajan E, Huang S (2009) STAT3 as a central regulator of tumor metastases. Curr Mol Med 9:626–633

    Article  CAS  PubMed  Google Scholar 

  273. Teng Y, Ross JL, Cowell JK (2014) The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 3:e28086

    PubMed  PubMed Central  Google Scholar 

  274. Wendt MK, Balanis N, Carlin CR et al (2014) STAT3 and epithelial–mesenchymal transitions in carcinomas. JAKSTAT 3:e28975

    PubMed  PubMed Central  Google Scholar 

  275. Kim E, Kim M, Woo DH et al (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23:839–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Lee HJ, Zhuang G, Cao Y et al (2014) Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26:207–221

    Article  CAS  PubMed  Google Scholar 

  277. Kotenko SV, Pestka S (2000) Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19:2557–2565

    Article  CAS  PubMed  Google Scholar 

  278. Long W, Wagner KU, Lloyd KC et al (2003) Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Development 130:5257–5268

    Article  CAS  PubMed  Google Scholar 

  279. Ramana CV, Gil MP, Schreiber RD et al (2002) Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23:96–101

    Article  CAS  PubMed  Google Scholar 

  280. Adamson AS, Collins K, Laurence A et al (2009) The Current STATus of lymphocyte signaling: new roles for old players. Curr Opin Immunol 21:161–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Cheng GZ, Zhang WZ, Sun M et al (2008) Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 283:14665–14673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Fukuda A, Wang SC, Morris JP et al (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19:441–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Yadav A, Kumar B, Datta J et al (2011) IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 9:1658–1667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Thieu VT, Yu Q, Chang HC et al (2008) Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29:679–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Matsumoto A, Masuhara M, Mitsui K et al (1997) CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89:3148–3154

    CAS  PubMed  Google Scholar 

  286. Matsumoto A, Seki Y, Kubo M et al (1999) Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2 protein-1 (CIS1) transgenic mice. Mol Cell Biol 19:6396–6407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Zhao P, Stephens JM (2013) Identification of STAT target genes in adipocytes. JAKSTAT 2:e23092

    PubMed  PubMed Central  Google Scholar 

  288. Wei L, Vahedi G, Sun HW et al (2010) Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32:840–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Kaplan MH, Grusby MJ (1998) Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 64:2–5

    CAS  PubMed  Google Scholar 

  290. Humphreys RC, Bierie B, Zhao L et al (2002) Deletion of Stat3 blocks mammary gland involution and extends functional competence of the secretory epithelium in the absence of lactogenic stimuli. Endocrinology 143:3641–3650

    Article  CAS  PubMed  Google Scholar 

  291. Lee JH, Kim TH, Oh SJ et al (2013) Signal transducer and activator of transcription-3 (Stat3) plays a critical role in implantation via progesterone receptor in uterus. FASEB J 27:2553–2563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Dobrian AD, Galkina EV, Ma Q et al (2013) STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation. Diabetes 62:4109–4121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Malin S, McManus S, Cobaleda C et al (2010) Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nat Immunol 11:171–179

    Article  CAS  PubMed  Google Scholar 

  294. Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI et al (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107:22617–22622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors recognize the support of an Alfred Deakin Postdoctoral Research Fellowship (CL) from Deakin University.

Author information

Authors and Affiliations

  1. School of Medicine, Deakin University, Melbourne, VIC, Australia

    Clifford Liongue, Rowena S. Lewis & Alister C. Ward

  2. Centre for Molecular and Medical Research, Deakin University, Melbourne, VIC, Australia

    Clifford Liongue, Rowena S. Lewis & Alister C. Ward

Authors
  1. Clifford Liongue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rowena S. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alister C. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alister C. Ward .

Editor information

Editors and Affiliations

  1. School of Medicine, Deakin University, Warun Ponds, Victoria, Australia

    Alister C. Ward

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Liongue, C., Lewis, R.S., Ward, A.C. (2016). STATs in Health and Disease. In: Ward, A. (eds) STAT Inhibitors in Cancer. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-42949-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-42949-6_1

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-42947-2

  • Online ISBN: 978-3-319-42949-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation