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Cited by 2,633Cytokine Signaling Pathways and InteractionsNF-κB Signaling PathwaysProtein Tyrosine Phosphatases

The JAK/STAT signaling pathway: from bench to clinic

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Hu, Xiaoyi, li, Jing, Fu, Maorong, Zhao, Xia, Wang, Wei·2021·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-021-00791-1PMC PMC8617206
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Abstract

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

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  • Activation of the JAK/STAT pathway plays a vital role in controlling proliferation, differentiation, migration, and apoptosis of tumor cells.

    “Activation of the JAK/STAT pathway plays a vital role in controlling the proliferation, differentiation, migration, and apoptosis of tumor cells [39, 63].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [63]

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  1. [1]Darnell JE Jr STATs and gene regulation Science 1997 277 1630 1635 9287210
  2. [2]Owen KL Brockwell NK Parker BS JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression Cancers 2019 11 2002 PMC6966445 31842362
  3. [3]Aittomäki S Pesu M Therapeutic targeting of the Jak/STAT pathway Basic Clin. Pharm. Toxicol. 2014 114 18 23 24164900
  4. [4]O’Shea JJ The JAK-STAT pathway: impact on human disease and therapeutic intervention Annu. Rev. Med. 2015 66 311 328 25587654 PMC5634336
  5. [5]Banerjee S Biehl A Gadina M Hasni S Schwartz DM JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects Drugs 2017 77 521 546 28255960 PMC7102286
  6. [6]Villarino AV Kanno Y O’Shea JJ Mechanisms and consequences of Jak-STAT signaling in the immune system Nat. Immunol. 2017 18 374 384 28323260 PMC11565648
  7. [7]Ivashkiv LB Donlin LT Regulation of type I interferon responses Nat. Rev. Immunol. 2014 14 36 49 24362405 PMC4084561
  8. [8]O’Shea JJ Plenge R JAK and STAT signaling molecules in immunoregulation and immune-mediated disease Immunity 2012 36 542 550 22520847 PMC3499974
  9. [9]Aaronson DS Horvath CM A road map for those who don’t know JAK-STAT Science 2002 296 1653 1655 12040185
  10. [11]Fu XY Kessler DS Veals SA Levy DE Darnell JE Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains Proc. Natl Acad. Sci. USA 1990 87 8555 8559 2236065 PMC54995
  11. [12]Fu XY A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s) Cell 1992 70 323 335 1638633
  12. [13]Fu XY A direct signaling pathway through tyrosine kinase activation of SH2 domain-containing transcription factors J. Leukoc. Biol. 1995 57 529 535 7722410
  13. [14]Shuai K Stark GR Kerr IM Darnell JE Jr A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma Science 1993 261 1744 1746 7690989
  14. [15]Zhong Z Wen Z Darnell JE Jr Stat3 and Stat4: members of the family of signal transducers and activators of transcription Proc. Natl Acad. Sci. USA 1994 91 4806 4810 7545930 PMC43877
  15. [16]Liu X Robinson GW Gouilleux F Groner B Hennighausen L Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue Proc. Natl Acad. Sci. USA 1995 92 8831 8835 7568026 PMC41061
  16. [17]Hou J An interleukin-4-induced transcription factor: IL-4 Stat Science 1994 265 1701 1706 8085155
  17. [18]Wilks AF Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction Proc. Natl Acad. Sci. USA 1989 86 1603 1607 2466296 PMC286746
  18. [19]Wilks AF Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase Mol. Cell. Biol. 1991 11 2057 2065 1848670 PMC359893
  19. [20]Krolewski JJ Lee R Eddy R Shows TB Dalla-Favera R Identification and chromosomal mapping of new human tyrosine kinase genes Oncogene 1990 5 277 282 2156206
  20. [21]Velazquez L Fellous M Stark GR Pellegrini S A protein tyrosine kinase in the interferon alpha/beta signaling pathway Cell 1992 70 313 322 1386289
  21. [22]Müller M The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction Nature 1993 366 129 135 8232552
  22. [23]Lai KS A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells J. Biol. Chem. 1995 270 25028 25036 7559633
  23. [24]Verbsky JW Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells J. Biol. Chem. 1996 271 13976 13980 8662778
  24. [25]Gurniak CB Berg LJ Murine JAK3 is preferentially expressed in hematopoietic tissues and lymphocyte precursor cells Blood 1996 87 3151 3160 8605329
  25. [26]Harpur AG Andres AC Ziemiecki A Aston RR Wilks AF JAK2, a third member of the JAK family of protein tyrosine kinases Oncogene 1992 7 1347 1353 1620548
  26. [27]Kawamura M Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes Proc. Natl Acad. Sci. USA 1994 91 6374 6378 8022790 PMC44204
  27. [28]Rane SG Reddy EP JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells Oncogene 1994 9 2415 2423 7518579
  28. [29]Takahashi T Shirasawa T Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases FEBS Lett. 1994 342 124 128 8143863
  29. [30]Ferrao R Lupardus PJ The janus kinase (JAK) FERM and SH2 domains: bringing specificity to JAK-receptor interactions Front. Endocrinol 2017 8 71 PMC5394478 28458652
  30. [31]Frank SJ Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor J. Biol. Chem. 1995 270 14776 14785 7540178
  31. [32]Velazquez L Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-alpha/beta and for signal transduction J. Biol. Chem. 1995 270 3327 3334 7531704
  32. [33]Leonard WJ O’Shea JJ Jaks and STATs: biological implications Annu Rev. Immunol. 1998 16 293 322 9597132
  33. [34]Rodig SJ Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses Cell 1998 93 373 383 9590172
  34. [35]Ihle JN Witthuhn BA Quelle FW Yamamoto K Silvennoinen O Signaling through the hematopoietic cytokine receptors Annu Rev. Immunol. 1995 13 369 398 7612228
  35. [36]Schindler C Strehlow I Cytokines and STAT signaling Adv. Pharm. 2000 47 113 174 10582086
  36. [37]Wu H Liu X Jaenisch R Lodish HF Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor Cell 1995 83 59 67 7553874
  37. [38]Neubauer H Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis Cell 1998 93 397 409 9590174
  38. [39]Russell SM Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID Science 1994 266 1042 1045 7973658
  39. [40]Cao X Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain Immunity 1995 2 223 238 7697543
  40. [41]Park SY Developmental defects of lymphoid cells in Jak3 kinase-deficient mice Immunity 1995 3 771 782 8777722
  41. [42]Saijo K Park SY Ishida Y Arase H Saito T Crucial role of Jak3 in negative selection of self-reactive T cells J. Exp. Med 1997 185 351 356 9016883 PMC2196119
  42. [43]Mogensen KE Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-α/β and for signal transduction J. Biol. Chem. 1995 270 3327 3334 7531704
  43. [44]Stahl N Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components Science 1994 263 92 95 8272873
  44. [45]Finbloom DS Winestock KD IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes J. Immunol. 1995 155 1079 1090 7543512
  45. [46]Bacon CM Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12 J. Exp. Med. 1995 181 399 404 7528775 PMC2191828
  46. [47]Welham MJ Learmonth L Bone H Schrader JW Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin J. Biol. Chem. 1995 270 12286 12296 7744881
  47. [48]Watford WT O’Shea JJ Human tyk2 kinase deficiency: another primary immunodeficiency syndrome Immunity 2006 25 695 697 17098200
  48. [49]Karaghiosoff M Partial impairment of cytokine responses in Tyk2-deficient mice Immunity 2000 13 549 560 11070173
  49. [50]Minegishi Y Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity Immunity 2006 25 745 755 17088085
  50. [51]Seto Y Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice J. Immunol. 2003 170 1077 1083 12517976
  51. [52]Fu XY Schindler C Improta T Aebersold R Darnell JE Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction Proc. Natl Acad. Sci. USA 1992 89 7840 7843 1502204 PMC49807
  52. [53]Hou J Schindler U Henzel WJ Wong SC McKnight SL Identification and purification of human Stat proteins activated in response to interleukin-2 Immunity 1995 2 321 329 7719937
  53. [54]Mui AL Wakao H O’Farrell AM Harada N Miyajima A Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs EMBO J. 1995 14 1166 1175 7720707 PMC398194
  54. [55]Zhong Z Wen Z Darnell JE Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6 Science 1994 264 95 98 8140422
  55. [56]Horvath CM STAT proteins and transcriptional responses to extracellular signals Trends Biochem. Sci. 2000 25 496 502 11050435
  56. [57]Murphy TL Geissal ED Farrar JD Murphy KM Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation Mol. Cell Biol. 2000 20 7121 7131 10982828 PMC86263
  57. [58]Shuai K Modulation of STAT signaling by STAT-interacting proteins Oncogene 2000 19 2638 2644 10851063
  58. [59]Vinkemeier U Moarefi I Darnell JE Jr Kuriyan J Structure of the amino-terminal protein interaction domain of STAT-4 Science 1998 279 1048 1052 9461439
  59. [60]Begitt A Meyer T van Rossum M Vinkemeier U Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain Proc. Natl Acad. Sci. USA 2000 97 10418 10423 10973496 PMC27039
  60. [61]Collum RG Brutsaert S Lee G Schindler C A Stat3-interacting protein (StIP1) regulates cytokine signal transduction Proc. Natl Acad. Sci. USA 2000 97 10120 10125 10954736 PMC27739
  61. [62]Horvath CM Stark GR Kerr IM Darnell JE Jr Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex Mol. Cell Biol. 1996 16 6957 6964 8943351 PMC231699
  62. [63]Kisseleva T Bhattacharya S Braunstein J Schindler CW Signaling through the JAK/STAT pathway, recent advances and future challenges Gene 2002 285 1 24 12039028
  63. [64]Zhang JG The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation Proc. Natl Acad. Sci. USA 1999 96 2071 2076 10051596 PMC26738
  64. [65]Zhang T Kee WH Seow KT Fung W Cao X The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6 Mol. Cell Biol. 2000 20 7132 7139 10982829 PMC86266
  65. [66]Zhu M John S Berg M Leonard WJ Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling Cell 1999 96 121 130 9989503
  66. [67]Yang E Wen Z Haspel RL Zhang JJ Darnell JE Jr The linker domain of Stat1 is required for gamma interferon-driven transcription. Mol Cell Biol. 1999 19 5106 5112 PMC84353 10373559
  67. [68]Kawata T SH2 signaling in a lower eukaryote: a STAT protein that regulates stalk cell differentiation in Dictyostelium Cell 1997 89 909 916 9200609
  68. [69]Barahmand-Pour F Meinke A Groner B Decker T Jak2-Stat5 interactions analyzed in yeast J. Biol. Chem. 1998 273 12567 12575 9575217
  69. [70]Chen X Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA Cell 1998 93 827 839 9630226
  70. [71]Gupta S The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals EMBO J. 1996 15 1075 1084 8605877 PMC450005
  71. [72]Shuai K Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions Cell 1994 76 821 828 7510216
  72. [73]Schindler C Fu XY Improta T Aebersold R Darnell JE Jr 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 1992 89 7836 7839 1502203 PMC49806
  73. [74]Müller M Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways EMBO J. 1993 12 4221 4228 7693454 PMC413716
  74. [75]Dimberg A Karlberg I Nilsson K Öberg F Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells Blood 2003 102 254 261 12637327
  75. [76]Schlee M C-myc activation impairs the NF-kappaB and the interferon response: implications for the pathogenesis of Burkitt’s lymphoma Int. J. Cancer 2007 120 1387 1395 17211884
  76. [77]Dimberg A Nilsson K Öberg F Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts Blood 2000 96 2870 2878 11023524
  77. [78]Takayanagi H Kim S Koga T Taniguchi T Stat1-mediated cytoplasmic attenuation in osteoimmunology J. Cell. Biochem. 2005 94 232 240 15546140
  78. [79]Lee C-K Smith E Gimeno R Gertner R Levy DE STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-γ J. Immunol. 2000 164 1286 1292 10640742
  79. [80]Wold WS Toth K Adenovirus vectors for gene therapy, vaccination and cancer gene therapy Curr. Gene Ther. 2013 13 421 433 24279313 PMC4507798
  80. [81]Gu W Roeder RG Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain Cell 1997 90 595 606 9288740
  81. [82]Xu X Fu XY Plate J Chong AS IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression Cancer Res. 1998 58 2832 2837 9661898
  82. [83]Stephanou A Brar BK Knight RA Latchman DS Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters Cell Death Differ. 2000 7 329 330 10866494
  83. [84]Dovhey SE Ghosh NS Wright KL Loss of interferon-gamma inducibility of TAP1 and LMP2 in a renal cell carcinoma cell line Cancer Res. 2000 60 5789 5796 11059775
  84. [85]Kovacic B STAT1 acts as a tumor promoter for leukemia development Cancer Cell 2006 10 77 87 16843267
  85. [86]Chatterjee-Kishore M Kishore R Hicklin DJ Marincola FM Ferrone S Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression J. Biol. Chem. 1998 273 16177 16183 9632673
  86. [87]Najjar I STAT1-dependent IgG cell-surface expression in a human B cell line derived from a STAT1-deficient patient J. Leukoc. Biol. 2010 87 1145 1152 20200400
  87. [88]Yoshimoto T Induction of IgG2a class switching in B cells by IL-27 J. Immunol. 2004 173 2479 2485 15294962
  88. [89]Dupuis S Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency Nat. Genet. 2003 33 388 391 12590259
  89. [90]Schindler C Plumlee C Inteferons pen the JAK–STAT pathway Semin. Cell Dev. Biol. 2008 19 311 318 18765289 PMC2741134
  90. [91]Wang Y A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses Cell Res. 2021 31 206 218 32759968 PMC7405385
  91. [92]Park C Li S Cha E Schindler C Immune response in Stat2 knockout mice Immunity 2000 13 795 804 11163195
  92. [93]Qureshy, Z., Johnson, D. E. & Grandis, J. R. Targeting the JAK/STAT pathway in solid tumors. J. Cancer Metastasis Treat6 (2020). PMC7845926 33521321
  93. [94]Maritano D The STAT3 isoforms alpha and beta have unique and specific functions Nat. Immunol. 2004 5 401 409 15021879
  94. [96]Schaefer TS Sanders LK Nathans D Cooperative transcriptional activity of Jun and Stat3 beta, a short form of Stat3 Proc. Natl Acad. Sci. USA 1995 92 9097 9101 7568080 PMC40931
  95. [98]Heinrich PC Behrmann I Müller-Newen G Schaper F Graeve L Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway Biochemical J. 1998 334 Pt 2 297 314 PMC1219691 9716487
  96. [99]Ruff-Jamison S Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver J. Biol. Chem. 1994 269 21933 21935 8071311
  97. [100]Zhang M A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis Nature 2020 586 434 439 33029007 PMC7874492
  98. [101]Kortylewski M Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity Nat. Med. 2005 11 1314 1321 16288283
  99. [102]Ostrand-Rosenberg S Sinha P Myeloid-derived suppressor cells: linking inflammation and cancer J. Immunol. 2009 182 4499 4506 19342621 PMC2810498
  100. [103]Bromberg JF Stat3 as an oncogene Cell 1999 98 295 303 10458605
  101. [104]Yu H Kortylewski M Pardoll D Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment Nat. Rev. Immunol. 2007 7 41 51 17186030
  102. [105]Catlett-Falcone R Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells Immunity 1999 10 105 115 10023775
  103. [106]Shao, F., Pang, X. & Baeg, G. H. Targeting the JAK/STAT signaling pathway for breast cancer. Curr. Med. Chem.10.2174/0929867328666201207202012 (2020). 33290193 · DOI
  104. [107]Avalle L Camporeale A Camperi A Poli V STAT3 in cancer: a double edged sword Cytokine 2017 98 42 50 28579221
  105. [108]Niu G Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo Cancer Res. 1999 59 5059 5063 10537273
  106. [109]Xu G Zhang C Zhang J Dominant negative STAT3 suppresses the growth and invasion capability of human lung cancer cells Mol. Med Rep. 2009 2 819 824 21475907
  107. [110]Yang L Targeting cancer stem cell pathways for cancer therapy Signal Transduct. Target. Ther. 2020 5 8 32296030 PMC7005297
  108. [111]Miyagi T High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells J. Exp. Med. 2007 204 2383 2396 17846149 PMC2118450
  109. [112]Thieu VT Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination Immunity 2008 29 679 690 18993086 PMC2768040
  110. [113]Weinstein JS STAT4 and T-bet control follicular helper T cell development in viral infections J. Exp. Med. 2018 215 337 355 29212666 PMC5748849
  111. [114]Murray PJ The JAK-STAT signaling pathway: input and output integration J. Immunol. 2007 178 2623 2629 17312100
  112. [115]Schindler C Levy DE Decker T JAK-STAT signaling: from interferons to cytokines J. Biol. Chem. 2007 282 20059 20063 17502367
  113. [116]Soldaini E DNA binding site selection of dimeric and tetrameric Stat5 proteins reveals a large repertoire of divergent tetrameric Stat5a binding sites Mol. Cell Biol. 2000 20 389 401 10594041 PMC85094
  114. [117]Lin JX Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells Nat. Commun. 2017 8 017 01477 PMC5673064 29105654
  115. [118]Azam M Interleukin-3 signals through multiple isoforms of Stat5 EMBO J. 1995 14 1402 1411 7537213 PMC398225
  116. [119]Wakao H Gouilleux F Groner B Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response EMBO J. 1995 14 854 855 7882987 PMC398153
  117. [120]Lin JX Leonard WJ The role of Stat5a and Stat5b in signaling by IL-2 family cytokines Oncogene 2000 19 2566 2576 10851055
  118. [121]Liu X Stat5a is mandatory for adult mammary gland development and lactogenesis Genes Dev. 1997 11 179 186 9009201
  119. [122]Lin JX Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function Immunity 2012 36 586 599 22520852 PMC3551341
  120. [123]Pericle F Immunocompromised tumor-bearing mice show a selective loss of STAT5a/b expression in T and B lymphocytes J. Immunol. 1997 159 2580 2585 9300676
  121. [124]Refaeli Y Van Parijs L London CA Tschopp J Abbas AK Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis Immunity 1998 8 615 623 9620682
  122. [125]Van Parijs L Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death Immunity 1999 11 281 288 10514006
  123. [126]Mikita T Daniel C Wu P Schindler U Mutational analysis of the STAT6 SH2 domain J. Biol. Chem. 1998 273 17634 17642 9651359
  124. [127]Chen H Activation of STAT6 by STING is critical for antiviral innate immunity Cell 2011 147 436 446 22000020
  125. [128]Patel BK Pierce JH LaRochelle WJ Regulation of interleukin 4-mediated signaling by naturally occurring dominant negative and attenuated forms of human Stat6 Proc. Natl Acad. Sci. USA 1998 95 172 177 9419348 PMC18165
  126. [129]Duetsch G STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study Hum. Mol. Genet. 2002 11 613 621 11912176
  127. [130]Zhu J Paul WE CD4 T cells: fates, functions, and faults Blood 2008 112 1557 1569 18725574 PMC2518872
  128. [131]Shimoda K Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene Nature 1996 380 630 633 8602264
  129. [132]Kaplan MH Schindler U Smiley ST Grusby MJ Stat6 is required for mediating responses to IL-4 and for development of Th2 cells Immunity 1996 4 313 319 8624821
  130. [133]Sasaki K Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo J. Immunol. 2008 181 104 108 18566374 PMC2596982
  131. [134]Tenhumberg S gp130 dimerization in the absence of ligand: preformed cytokine receptor complexes Biochem. Biophys. Res. Commun. 2006 346 649 657 16774741
  132. [135]Livnah O Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation Science 1999 283 987 990 9974392
  133. [136]Remy I Wilson IA Michnick SW Erythropoietin receptor activation by a ligand-induced conformation change Science 1999 283 990 993 9974393
  134. [137]Naismith JH Devine TQ Brandhuber BJ Sprang SR Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor J. Biol. Chem. 1995 270 13303 13307 7768931
  135. [138]Kramer JM Evidence for ligand-independent multimerization of the IL-17 receptor J. Immunol. 2006 176 711 715 16393951 PMC2973994
  136. [139]Krause CD Interactions among the components of the interleukin-10 receptor complex Biochem. Biophys. Res. Commun. 2006 340 377 385 16364239
  137. [140]Brooks AJ Mechanism of activation of protein kinase JAK2 by the growth hormone receptor Science 2014 344 1249783 24833397
  138. [141]Durham GA Williams JJL Nasim MT Palmer TM Targeting SOCS proteins to control JAK-STAT signalling in disease Trends Pharmacol. Sci. 2019 40 298 308 30948191
  139. [143]Li WX Canonical and non-canonical JAK-STAT signaling Trends Cell Biol. 2008 18 545 551 18848449 PMC3082280
  140. [144]Shi S JAK signaling globally counteracts heterochromatic gene silencing Nat. Genet. 2006 38 1071 1076 16892059 PMC3092431
  141. [145]Shi S Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability Nat. Cell Biol. 2008 10 489 496 18344984 PMC3083919
  142. [146]Ogawa H Ishiguro K Gaubatz S Livingston DM Nakatani Y A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells Science 2002 296 1132 1136 12004135
  143. [147]Braig M Oncogene-induced senescence as an initial barrier in lymphoma development Nature 2005 436 660 665 16079837
  144. [149]Christova R P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFN J. Cell Sci. 2007 120 3262 3270 17726060
  145. [150]Shi M Lin TH Appell KC Berg LJ Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation Immunity 2008 28 763 773 18549798 PMC2587400
  146. [151]Lai SY Johnson FM Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches Drug Resist. Updat. 2010 13 67 78 20471303
  147. [152]Limnander A Rothman PB Abl oncogene bypasses normal regulation of Jak/STAT activation Cell Cycle 2004 3 1486 1488 15611644
  148. [153]Han Y Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma Blood 2006 108 2796 2803 16825495
  149. [154]Coppo P BCR-ABL activates STAT3 via JAK and MEK pathways in human cells Br. J. Haematol. 2006 134 171 179 16846476
  150. [155]Yu CL Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein Science 1995 269 81 83 7541555
  151. [156]Fu XY Zhang JJ Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter Cell 1993 74 1135 1145 8402883
  152. [157]Ruff-Jamison S Chen K Cohen S Epidermal growth factor induces the tyrosine phosphorylation and nuclear translocation of Stat 5 in mouse liver Proc. Natl Acad. Sci. USA 1995 92 4215 4218 7538664 PMC41914
  153. [158]Stöcklin E Wissler M Gouilleux F Groner B Functional interactions between Stat5 and the glucocorticoid receptor Nature 1996 383 726 728 8878484
  154. [159]Horvai AE Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300 Proc. Natl Acad. Sci. USA 1997 94 1074 1079 9037008 PMC19746
  155. [160]Wakioka T APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl Leukemia 1999 13 760 767 10374881
  156. [161]Tanaka N Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediated by cytokines J. Biol. Chem. 1999 274 19129 19135 10383417
  157. [162]Yoshimura A A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors EMBO J. 1995 14 2816 2826 7796808 PMC398400
  158. [164]Yasukawa H The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop EMBO J. 1999 18 1309 1320 10064597 PMC1171221
  159. [165]Okumura F Joo-Okumura A Nakatsukasa K Kamura T The role of cullin 5-containing ubiquitin ligases Cell Div. 2016 11 1 27030794 PMC4812663
  160. [166]Tamiya T Kashiwagi I Takahashi R Yasukawa H Yoshimura A Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3 Arterioscler Thromb. Vasc. Biol. 2011 31 980 985 21508344
  161. [167]Mohr SE Boswell RE Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster Gene 1999 229 109 116 10095110
  162. [168]Takahashi Y Kahyo T Toh-e A Yasuda H Kikuchi Y Yeast Ull1/Siz1 is a novel SUMO1/Smt3 ligase for septin components and functions as an adaptor between conjugating enzyme and substrates J. Biol. Chem. 2001 276 48973 48977 11577116
  163. [169]Sonnenblick A Levy C Razin E Interplay between MITF, PIAS3, and STAT3 in mast cells and melanocytes Mol. Cell. Biol. 2004 24 10584 10592 15572665 PMC533964
  164. [170]Rogers RS Horvath CM Matunis MJ SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation J. Biol. Chem. 2003 278 30091 30097 12764129
  165. [171]Tussié-Luna MI Bayarsaihan D Seto E Ruddle FH Roy AL Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxbeta Proc. Natl Acad. Sci. USA 2002 99 12807 12812 12239342 PMC130541
  166. [172]Sachdev S PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies Genes Dev. 2001 15 3088 3103 11731474 PMC312834
  167. [173]Ungureanu D PIAS proteins promote SUMO-1 conjugation to STAT1 Blood 2003 102 3311 3313 12855578
  168. [174]Liu B PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity Nat. Immunol. 2004 5 891 898 15311277
  169. [175]ten Hoeve J Identification of a nuclear Stat1 protein tyrosine phosphatase Mol. Cell Biol. 2002 22 5662 5668 12138178 PMC133976
  170. [176]Ram PA Waxman DJ Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase J. Biol. Chem. 1997 272 17694 17702 9211920
  171. [177]Irie-Sasaki J CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling Nature 2001 409 349 354 11201744
  172. [178]Myers MP TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B J. Biol. Chem. 2001 276 47771 47774 11694501
  173. [179]Klingmuller U Lorenz U Cantley LC Neel BG Lodish HF Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals Cell 1995 80 729 738 7889566
  174. [181]Nakashima K Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300 Science 1999 284 479 482 10205054
  175. [182]Luo K Signaling cross talk between TGF-β/Smad and other signaling pathways Cold Spring Harb. Perspect. Biol 2017 9 a022137 27836834 PMC5204325
  176. [183]Biffi G IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma Cancer Discov. 2019 9 282 301 30366930 PMC6368881
  177. [184]Tang LY Transforming growth factor-β (TGF-β) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway J. Biol. Chem. 2017 292 4302 4312 28154170 PMC5354477
  178. [185]Wang G STAT3 selectively interacts with Smad3 to antagonize TGF-β signalling Oncogene 2016 35 4388 4398 26616859 PMC4885808
  179. [186]Bright JJ Sriram S TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes J. Immunol. 1998 161 1772 1777 9712043
  180. [188]Josten F Fuss B Feix M Meissner T Hoch M Cooperation of JAK/STAT and Notch signaling in the Drosophila foregut Dev. Biol. 2004 267 181 189 14975725
  181. [189]Liu W Singh SR Hou SX JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells J. Cell Biochem. 2010 109 992 999 20082318 PMC2893559
  182. [190]Assa-Kunik E Torres IL Schejter ED Johnston DS Shilo BZ Drosophila follicle cells are patterned by multiple levels of Notch signaling and antagonism between the Notch and JAK/STAT pathways Development 2007 134 1161 1169 17332535
  183. [191]Kamakura S Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling Nat. Cell Biol. 2004 6 547 554 15156153
  184. [192]Jin S Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ Oncogene 2013 32 4892 4902 23178494 PMC3795477
  185. [193]Krasilnikov M Ivanov VN Dong J Ronai Z ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis Oncogene 2003 22 4092 4101 12821943
  186. [194]Rädler PD Wehde BL Wagner KU Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells Mol. Cell Endocrinol. 2017 451 31 39 28495456 PMC5515553
  187. [195]Tasian SK Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia Blood 2012 120 833 842 22685175 PMC3412346
  188. [196]Zhang Q Lenardo MJ Baltimore D 30 years of NF-κB: a blossoming of relevance to human pathobiology Cell 2017 168 37 57 28086098 PMC5268070
  189. [197]Baud V Karin M Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls Nat. Rev. Drug Discov. 2009 8 33 40 19116625 PMC2729321
  190. [198]Grivennikov S IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer Cancer Cell 2009 15 103 113 19185845 PMC2667107
  191. [199]Kortylewski M Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment Cancer Cell 2009 15 114 123 19185846 PMC2673504
  192. [200]Wang L IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway J. Exp. Med. 2009 206 1457 1464 19564351 PMC2715087
  193. [201]Yu H Pardoll D Jove R STATs in cancer inflammation and immunity: a leading role for STAT3 Nat. Rev. Cancer 2009 9 798 809 19851315 PMC4856025
  194. [202]Lee H Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors Cancer Cell 2009 15 283 293 19345327 PMC2777654
  195. [203]Chen Z O’Shea JJ Th17 cells: a new fate for differentiating helper T cells Immunol. Res. 2008 41 87 102 18172584
  196. [204]Dalwadi H Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer Clin. Cancer Res. 2005 11 7674 7682 16278387
  197. [205]Bennett BL Cruz R Lacson RG Manning AM Interleukin-4 suppression of tumor necrosis factor alpha-stimulated E-selectin gene transcription is mediated by STAT6 antagonism of NF-kappaB J. Biol. Chem. 1997 272 10212 10219 9092569
  198. [206]Farlik M Nonconventional initiation complex assembly by STAT and NF-kappaB transcription factors regulates nitric oxide synthase expression Immunity 2010 33 25 34 20637660 PMC2914224
  199. [207]Savitsky D Tamura T Yanai H Taniguchi T Regulation of immunity and oncogenesis by the IRF transcription factor family Cancer Immunol. Immunother. 2010 59 489 510 20049431 PMC11030943
  200. [208]Levy DE Darnell JE Jr Stats: transcriptional control and biological impact Nat. Rev. Mol. Cell Biol. 2002 3 651 662 12209125

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Cited by

Sorted by citations

Authors
Hu, X., li, J., Fu, M., Zhao, X., & Wang, W.
Affiliations
Sichuan University (CN)
Corresponding author
  • Zhao, Xia
  • Wang, Wei
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-11-26
Volume
6
Issue
1
Pages
402-402
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-021-00791-1
PMC
PMC8617206
OpenAlex
W3216146155
Cited by
2,633
References
26
Citations by year
2026: 579 · 2025: 778 · 2024: 694 · 2023: 440 · 2022: 138 · 2021: 1 · 2020: 1 · 2019: 1
FWCI
38.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Science and Technology of the People’s Republic of China (2020YFC860200)
  • Department of Science and Technology of Sichuan Province (2020YFS0008)
  • National Natural Science Foundation of China (No. 81902662)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
JAK/STAT signaling, Janus kinase, signal transducer and activator of transcription, cancer, inflammation, autoimmune disease, JAK inhibitors, STAT inhibitors, dysregulated pathways
MeSH terms
Autoimmune Diseases, Humans, Neoplasm Proteins, Neoplasms, Signal Transduction, STAT Transcription Factors, Janus Kinases

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