SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use?

Cellular and Molecular Life Sciences

Volumn 73, Issue 17, 2016, Pages 3323-3336

  Mahony, R ^a   Ahmed, S ^a   Diskin, C ^a   Stevenson, N J ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Cancer; Diabetes; Infection; Janus kinase signal transduction and activator of transcription (JAK STAT); Rheumatoid arthritis; Suppressor of cytokine signalling (SOCS)

Indexed keywords

INTERLEUKIN 1; INTERLEUKIN 17; INTERLEUKIN 6; STAT1 PROTEIN; STAT3 PROTEIN; STAT4 PROTEIN; STAT5 PROTEIN; STAT6 PROTEIN; SUPPRESSOR OF CYTOKINE SIGNALING 3; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 2; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 6; CYTOKINE; JANUS KINASE; MICRORNA; STAT PROTEIN; SUPPRESSOR OF CYTOKINE SIGNALING;

BACTERIAL INFECTION; CARCINOGENESIS; CD4+ T LYMPHOCYTE; CYTOKINE PRODUCTION; DIABETES MELLITUS; DISEASE COURSE; HELPER CELL; HUMAN; IMMUNOREGULATION; INTRACELLULAR SIGNALING; LYMPHOCYTE DIFFERENTIATION; MOLECULAR PATHOLOGY; NEOPLASM; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; RHEUMATOID ARTHRITIS; UPREGULATION; VIRUS INFECTION; ANTAGONISTS AND INHIBITORS; GENETICS; METABOLISM; ONCOLYTIC VIROTHERAPY; PATHOLOGY; SIGNAL TRANSDUCTION;

ARTHRITIS, RHEUMATOID; CYTOKINES; HUMANS; JANUS KINASES; MICRORNAS; NEOPLASMS; ONCOLYTIC VIROTHERAPY; SIGNAL TRANSDUCTION; STAT TRANSCRIPTION FACTORS; SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS; VIRUS DISEASES;

EID: 84965042700     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2234-x     Document Type: Review

References (164)

1. Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465
2. Krebs DL, Hilton DJ (2001) SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19:378–387
3. Darnell J, Kerr I, Stark G (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421
4. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635
5. O’Shea JJ, Notarangelo LD, Johnston JA, Candotti F (1997) Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency. J Clin Immunol 17:431–447
6. Nicola NA, Greenhalgh CJ (2000) The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. Exp Hematol 28:1105–1112
7. Dalpke A, Heeg K, Bartz H, Baetz A (2008) Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins. Immunobiology 213:225–235
8. Qin H, Holdbrooks AT, Liu Y, Reynolds SL, Yanagisawa LL, Benveniste EN (2012) SOCS3 deficiency promotes M1 macrophage polarization and inflammation. J Immunol 189:3439–3448
9. Baker BJ, Akhtar LN, Benveniste EN (2009) SOCS1 and SOCS3 in the control of CNS immunity. Trends Immunol 30:392–400
10. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921
11. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (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
12. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, Starr R, Nicholson SE, Metcalf D, Nicola NA (1998) Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci USA 95:114–119
13. Piessevaux J, Lavens D, Peelman F, Tavernier J (2008) The many faces of the SOCS box. Cytokine Growth Factor Rev 19:371–381
14. Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A (2011) Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 31:980–985
15. Sass G, Shembade ND, Tiegs G (2005) Tumour necrosis factor alpha (TNF)-TNF receptor 1-inducible cytoprotective proteins in the mouse liver: relevance of suppressors of cytokine signalling. Biochem J 385:537–544
16. Stevenson NJ, Haan S, McClurg AE, McGrattan MJ, Armstrong MA, Heinrich PC, Johnston JA (2004) The chemoattractants, IL-8 and formyl-methionyl-leucyl-phenylalanine, regulate granulocyte colony-stimulating factor signaling by inducing suppressor of cytokine signaling-1 expression. J Immunol 173:3243–3249
17. Stevenson NJ, Addley MR, Ryan EJ, Boyd CR, Carroll HP, Paunovic V, Bursill CA, Miller HC, Channon KM, McClurg AE, Armstrong MA, Coulter WA, Greaves DR, Johnston JA (2009) CCL11 blocks IL-4 and GM-CSF signaling in hematopoietic cells and hinders dendritic cell differentiation via suppressor of cytokine signaling expression. J Leukoc Biol 85:289–297
18. Greenhalgh CJ, Alexander WS (2004) Suppressors of cytokine signalling and regulation of growth hormone action. Growth Horm IGF Res 14:200–206
19. Babon JJ, Kershaw NJ, Murphy JM, Varghese LN, Laktyushin A, Young SN, Lucet IS, Norton RS, Nicola NA (2012) Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity 36:239–250
20. Babon JJ, Nicola NA (2012) The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors 30:207–219
21. Linossi EM, Nicholson SE (2012) The SOCS box-adapting proteins for ubiquitination and proteasomal degradation. IUBMB Life 64:316–323
22. Kamura T, Sato S, Haque D, Liu L, Kaelin WG Jr, Conaway RC, Conaway JW (1998) The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev 12:3872–3881
23. Park SH, Kim KE, Hwang HY, Kim TY (2003) Regulatory effect of SOCS on NF-kappaB activity in murine monocytes/macrophages. DNA Cell Biol 22:131–139
24. Babon JJ, Sabo JK, Zhang J-G, Nicola NA, Norton RS (2009) The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression. J Mol Biol 387:162–174
25. Yoshimura A, Suzuki M, Sakaguchi R, Hanada T, Yasukawa H (2012) SOCS, inflammation, and autoimmunity. Front Immunol 3:20
26. Madonna S, Scarponi C, De Pita O, Albanesi C (2008) Suppressor of cytokine signaling 1 inhibits IFN-gamma inflammatory signaling in human keratinocytes by sustaining ERK1/2 activation. FASEB J 22:3287–3297
27. Lu Y, Fukuyama S, Yoshida R, Kobayashi T, Saeki K, Shiraishi H, Yoshimura A, Takaesu G (2006) Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. J Biol Chem 281:36683–36690
28. Stevenson NJ, McFarlane C, Ong ST, Nahlik K, Kelvin A, Addley MR, Long A, Greaves DR, O’Farrelly C, Johnston JA (2010) Suppressor of cytokine signalling (SOCS) 1 and 3 enhance cell adhesion and inhibit migration towards the chemokine eotaxin/CCL11. FEBS Lett 584:4469–4474
29. Collins AS, Ahmed S, Napoletano S, Schroeder M, Johnston JA, Hegarty JE, O’Farrelly C, Stevenson NJ (2014) Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-alpha responses. J Leukoc Biol 96:255–263
30. Auernhammer CJ, Chesnokova V, Bousquet C, Melmed S (1998) Pituitary corticotroph SOCS-3: novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion. Mol Endocrinol 12:954–961
31. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG Jr (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 275:40649–40657
32. Demoulin JB, Van Snick J, Renauld JC (2001) Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor. Cell Growth Differ 12:169–174
33. Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Haussinger D (2001) The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Biol Chem 382:1447–1453
34. Ronn SG, Hansen JA, Lindberg K, Karlsen AE, Billestrup N (2002) The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells. Mol Endocrinol 16:2124–2134
35. Denson LA, Held MA, Menon RK, Frank SJ, Parlow AF, Arnold DL (2003) Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Am J Physiol Gastrointest Liver Physiol 284:2
36. Yadav A, Kalita A, Dhillon S, Banerjee K (2005) JAK/STAT3 pathway is involved in survival of neurons in response to insulin-like growth factor and negatively regulated by suppressor of cytokine signaling-3. J Biol Chem 280:31830–31840
37. Song MM, Shuai K (1998) The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem 273:35056–35062
38. Yamamoto K, Yamaguchi M, Miyasaka N, Miura O (2003) SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor beta2 subunit. Biochem Biophys Res Commun 310:1188–1193
39. Cohney SJ, Sanden D, Cacalano NA, Yoshimura A, Mui A, Migone TS, Johnston JA (1999) SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Mol Cell Biol 19:4980–4988
40. Hebenstreit D, Luft P, Schmiedlechner A, Duschl A, Horejs-Hoeck J (2005) SOCS-1 and SOCS-3 inhibit IL-4 and IL-13 induced activation of Eotaxin-3/CCL26 gene expression in HEK293 cells. Mol Immunol 42:295–303
41. Frobose H, Ronn SG, Heding PE, Mendoza H, Cohen P, Mandrup-Poulsen T, Billestrup N (2006) Suppressor of cytokine signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Mol Endocrinol 20:1587–1596
42. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T (1997) Structure and function of a new STAT-induced STAT inhibitor. Nature 387:924–929
43. Ramgolam VS, Markovic-Plese S (2011) Regulation of suppressors of cytokine signaling as a therapeutic approach in autoimmune diseases, with an emphasis on multiple sclerosis. J Signal Transduct 2011:635721
44. Whitmarsh RJ, Gray CM, Gregg B, Christian DA, May MJ, Murray PJ, Hunter CA (2011) A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host Microbe 10:224–236
45. Yan C, Ward PA, Wang X, Gao H (2013) Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein delta pathway. FASEB J. doi:10.1096/fj.12-225797
46. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4:551–556
47. Liu X, Zhang Y, Yu Y, Yang X, Cao X (2008) SOCS3 promotes TLR4 response in macrophages by feedback inhibiting TGF-beta1/Smad3 signaling. Mol Immunol 45:1405–1413
48. Yu CR, Mahdi RM, Ebong S, Vistica BP, Gery I, Egwuagu CE (2003) Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells. J Biol Chem 278:29752–29759
49. Egwuagu CE, Yu CR, Zhang M, Mahdi RM, Kim SJ, Gery I (2002) Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J Immunol 168:3181–3187
50. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O’Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M (2003) SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 9:1047–1054
51. Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A (2006) Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1. J Exp Med 203:1021–1031
52. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O’Shea JJ (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 103:8137–8142
53. Veenbergen S, Bennink MB, de Hooge AS, Arntz OJ, Smeets RL, van den Berg WB, van de Loo FA (2008) Splenic suppressor of cytokine signaling 3 transgene expression affects T cell responses and prevents development of collagen-induced arthritis. Arthritis Rheum 58:3742–3752
54. van de Loo FA, Veenbergen S, van den Brand B, Bennink MB, Blaney-Davidson E, Arntz OJ, van Beuningen HM, van der Kraan PM, van den Berg WB (2012) Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function. Arthritis Rheum 64:3313–3323
55. Akhtar LN, Benveniste EN (2011) Viral exploitation of host SOCS protein functions. J Virol 85:1912–1921
56. Xu WP, Li WD (2011) SOCS3: a potential therapeutic target for many human diseases. Yao Xue Xue Bao 46:747–752
57. Fujii K, Tsuji M, Tajima M (1999) Rheumatoid arthritis: a synovial disease? Ann Rheum Dis 58:727–730
58. Wong PK, Egan PJ, Croker BA, O’Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP (2006) SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest 116:1571–1581
59. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219
60. Paradowska A, Masliniski W, Grzybowska-Kowalczyk A, Lacki J (2007) The function of interleukin 17 in the pathogenesis of rheumatoid arthritis. Arch Immunol Ther Exp (Warsz) 55:329–334
61. Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108:1781–1788
62. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440
63. Tsao JT, Kuo CC, Lin SC (2008) The analysis of CIS, SOCS1, SOSC2 and SOCS3 transcript levels in peripheral blood mononuclear cells of systemic lupus erythematosus and rheumatoid arthritis patients. Clin Exp Med 8:179–185
64. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10:4025–4031
65. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker J, Bijl H, Ghrayeb J et al (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 36:1681–1690
66. Rottapel R (2001) Putting the brakes on arthritis: can suppressors of cytokine signaling (SOCS) suppress rheumatoid arthritis? J Clin Invest 108:1745–1747
67. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141–147
68. Wiland P, Sokalska-Jurkiewicz M, Madej M (2008) The role of Jak/STAT signaling in rheumatoid arthritis. Adv Clin Exp Med 17:447–452
69. Wang F, Sengupta TK, Zhong Z, Ivashkiv LB (1995) Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J Exp Med 182:1825–1831
70. Walker JG, Smith MD (2005) The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 32:1650–1653
71. de Hooge AS, van de Loo FA, Koenders MI, Bennink MB, Arntz OJ, Kolbe T, van den Berg WB (2004) Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice. Arthritis Rheum 50:2014–2023
72. Atsumi T, Ishihara K, Kamimura D, Ikushima H, Ohtani T, Hirota S, Kobayashi H, Park SJ, Saeki Y, Kitamura Y, Hirano T (2002) A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J Exp Med 196:979–990
73. Rieusset J, Bouzakri K, Chevillotte E, Ricard N, Jacquet D, Bastard JP, Laville M, Vidal H (2004) Suppressor of cytokine signaling 3 expression and insulin resistance in skeletal muscle of obese and type 2 diabetic patients. Diabetes 53:2232–2241
74. Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, Rentfro A, McCormick JB, Fisher-Hoch SP (2012) Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine 57:136–142
75. Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276:47944–47949
76. Torisu T, Sato N, Yoshiga D, Kobayashi T, Yoshioka T, Mori H, Iida M, Yoshimura A (2007) The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells 12:143–154
77. Jorgensen SB, O’Neill HM, Sylow L, Honeyman J, Hewitt KA, Palanivel R, Fullerton MD, Oberg L, Balendran A, Galic S, van der Poel C, Trounce IA, Lynch GS, Schertzer JD, Steinberg GR (2013) Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes 62:56–64
78. Yang Z, Hulver M, McMillan RP, Cai L, Kershaw EE, Yu L, Xue B, Shi H (2012) Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PLoS One 7:e47493
79. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278:13740–13746
80. Tokita T, Maesawa C, Kimura T, Kotani K, Takahashi K, Akasaka T, Masuda T (2007) Methylation status of the SOCS3 gene in human malignant melanomas. Int J Oncol 30:689–694
81. Shi H, Cave B, Inouye K, Bjorbaek C, Flier JS (2006) Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes 55:699–707
82. Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277:42394–42398
83. Garcia-Sastre A (2001) Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses. Virology 279:375–384
84. Alcami A, Koszinowski UH (2000) Viral mechanisms of immune evasion. Immunol Today 21:447–455
85. Smith GL, Benfield CT, Maluquer de Motes C, Mazzon M, Ember SW, Ferguson BJ, Sumner RP (2013) Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 94:2367–2392
86. Stevenson NJ, Bourke NM, Ryan EJ, Binder M, Fanning L, Johnston JA, Hegarty JE, Long A, O’Farrelly C (2013) Hepatitis C virus targets the interferon-alpha JAK/STAT pathway by promoting proteasomal degradation in immune cells and hepatocytes. FEBS Lett 587:1571–1578
87. Huang Y, Feld JJ, Sapp RK, Nanda S, Lin JH, Blatt LM, Fried MW, Murthy K, Liang TJ (2007) Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology 132:733–744
88. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Haussinger D (2003) IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J 17:488–490
89. Yokota S, Yokosawa N, Okabayashi T, Suzutani T, Fujii N (2005) Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 confers efficient viral replication. Virology 338:173–181
90. Yokota S, Yokosawa N, Okabayashi T, Suzutani T, Miura S, Jimbow K, Fujii N (2004) Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 contributes to inhibition of the interferon signaling pathway. J Virol 78:6282–6286
91. Kim KA, Lin W, Tai AW, Shao RX, Weinberg E, De Sa Borges CB, Bhan AK, Zheng H, Kamegaya Y, Chung RT (2009) Hepatic SOCS3 expression is strongly associated with non-response to therapy and race in HCV and HCV/HIV infection. J Hepatol 50:705–711
92. Zhu H, Nelson DR, Crawford JM, Liu C (2005) Defective Jak-Stat activation in hepatoma cells is associated with hepatitis C viral IFN-α resistance. J Interferon Cytokine Res 25:528–539
93. Shao RX, Zhang L, Peng LF, Sun E, Chung WJ, Jang JY, Tsai WL, Hyppolite G, Chung RT (2010) Suppressor of cytokine signaling 3 suppresses hepatitis C virus replication in an mTOR-dependent manner. J Virol 84:6060–6069
94. Moutsopoulos NM, Vazquez N, Greenwell-Wild T, Ecevit I, Horn J, Orenstein J, Wahl SM (2006) Regulation of the tonsil cytokine milieu favors HIV susceptibility. J Leukoc Biol 80:1145–1155
95. Ryo A, Tsurutani N, Ohba K, Kimura R, Komano J, Nishi M, Soeda H, Hattori S, Perrem K, Yamamoto M, Chiba J, Mimaya J, Yoshimura K, Matsushita S, Honda M, Yoshimura A, Sawasaki T, Aoki I, Morikawa Y, Yamamoto N (2008) SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag. Proc Natl Acad Sci USA 105:294–299
96. Akhtar LN, Qin H, Muldowney MT, Yanagisawa LL, Kutsch O, Clements JE, Benveniste EN (2010) Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. J Immunol 185:2393–2404
97. Miller RC, Schlaepfer E, Baenziger S, Crameri R, Zeller S, Byland R, Audige A, Nadal D, Speck RF (2011) HIV interferes with SOCS-1 and -3 expression levels driving immune activation. Eur J Immunol 41:1058–1069
98. Palese P (2004) Influenza: old and new threats. Nat Med 10:S82–S87
99. Jia D, Rahbar R, Chan RW, Lee SM, Chan MC, Wang BX, Baker DP, Sun B, Peiris JS, Nicholls JM, Fish EN (2010) Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling. PLoS One 5:e13927
100. Pauli EK, Schmolke M, Wolff T, Viemann D, Roth J, Bode JG, Ludwig S (2008) Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog 4:e1000196
101. Hashimoto K, Ishibashi K, Ishioka K, Zhao D, Sato M, Ohara S, Abe Y, Kawasaki Y, Sato Y, Yokota S, Fujii N, Peebles RS Jr, Hosoya M, Suzutani T (2009) RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules. Virology 391:162–170
102. Moore EC, Barber J, Tripp RA (2008) Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15). Virol J 5:116
103. Oshansky CM, Krunkosky TM, Barber J, Jones LP, Tripp RA (2009) Respiratory syncytial virus proteins modulate suppressors of cytokine signaling 1 and 3 and the type I interferon response to infection by a toll-like receptor pathway. Viral Immunol 22:147–161
104. Elliott J, Lynch OT, Suessmuth Y, Qian P, Boyd CR, Burrows JF, Buick R, Stevenson NJ, Touzelet O, Gadina M, Power UF, Johnston JA (2007) Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. J Virol 81:3428–3436
105. Stoiber D, Kovarik P, Cohney S, Johnston JA, Steinlein P, Decker T (1999) Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. J Immunol 163:2640–2647
106. Bussmeyer U, Sarkar A, Broszat K, Ludemann T, Moller S, van Zandbergen G, Bogdan C, Behnen M, Dumler JS, von Loewenich FD, Solbach W, Laskay T (2010) Impairment of gamma interferon signaling in human neutrophils infected with Anaplasma phagocytophilum. Infect Immun 78:358–363
107. Covert J, Mathison AJ, Eskra L, Banai M, Splitter G (2009) Brucella melitensis, B. neotomae and B. ovis elicit common and distinctive macrophage defense transcriptional responses. Exp Biol Med 234:1450–1467
108. Latvala S, Miettinen M, Kekkonen RA, Korpela R, Julkunen I (2011) Lactobacillus rhamnosus GG and Streptococcus thermophilus induce suppressor of cytokine signalling 3 (SOCS3) gene expression directly and indirectly via interleukin-10 in human primary macrophages. Clin Exp Immunol 165:94–103
109. Dennis VA, Jefferson A, Singh SR, Ganapamo F, Philipp MT (2006) Interleukin-10 anti-inflammatory response to Borrelia burgdorferi, the agent of Lyme disease: a possible role for suppressors of cytokine signaling 1 and 3. Infect Immun 74:5780–5789
110. Cha B, Kim KH, Matsui H, Kim H (2007) Expression of suppressors of cytokine signaling-3 in Helicobacter pylori-infected rat gastric mucosal RGM-1cells. Ann N Y Acad Sci 1096:24–28
111. Narayana Y, Balaji KN (2008) NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages. J Biol Chem 283:12501–12511
112. St John AL, Abraham SN (2009) Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines. Nat Med 15:1259–1265
113. Mistry R, Cliff JM, Clayton CL, Beyers N, Mohamed YS, Wilson PA, Dockrell HM, Wallace DM, van Helden PD, Duncan K, Lukey PT (2007) Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. J Infect Dis 195:357–365
114. Nair S, Pandey AD, Mukhopadhyay S (2011) The PPE18 protein of Mycobacterium tuberculosis inhibits NF-kappaB/rel-mediated proinflammatory cytokine production by upregulating and phosphorylating suppressor of cytokine signaling 3 protein. J Immunol 186:5413–5424
115. Carow B, Reuschl AK, Gavier-Widen D, Jenkins BJ, Ernst M, Yoshimura A, Chambers BJ, Rottenberg ME (2013) Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis. PLoS Pathog 9:4
116. Masood KI, Rottenberg ME, Salahuddin N, Irfan M, Rao N, Carow B, Islam M, Hussain R, Hasan Z (2013) Expression of M. tuberculosis-induced suppressor of cytokine signaling (SOCS) 1, SOCS3, FoxP3 and secretion of IL-6 associates with differing clinical severity of tuberculosis. BMC Infect Dis 13:1471–2334
117. Rottenberg ME, Carow B (2014) SOCS3 and STAT3, major controllers of the outcome of infection with Mycobacterium tuberculosis. Semin Immunol 26:518–532
118. Liu E, Cote JF, Vuori K (2003) Negative regulation of FAK signaling by SOCS proteins. EMBO J 22:5036–5046
119. He B, You L, Uematsu K, Zang K, Xu Z, Lee AY, Costello JF, McCormick F, Jablons DM (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100:14133–14138
120. Weber A, Hengge UR, Bardenheuer W, Tischoff I, Sommerer F, Markwarth A, Dietz A, Wittekind C, Tannapfel A (2005) SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene 24:6699–6708
121. Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24:6406–6417
122. Ying M, Li D, Yang L, Wang M, Wang N, Chen Y, He M, Wang Y (2010) Loss of SOCS3 expression is associated with an increased risk of recurrent disease in breast carcinoma. J Cancer Res Clin Oncol 136:1617–1626
123. Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G, Riemenschneider MJ (2011) SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol 122:241–251
124. Iwahori K, Serada S, Fujimoto M, Nomura S, Osaki T, Lee CM, Mizuguchi H, Takahashi T, Ripley B, Okumura M, Kawase I, Kishimoto T, Naka T (2011) Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma. Int J Cancer 129:1005–1017
125. Villa-Moruzzi E (2011) Tyrosine phosphatases in the HER2-directed motility of ovarian cancer cells: involvement of PTPN12, ERK5 and FAK. Anal Cell Pathol 34:101–112
126. Geng D, Zhao W, Feng Y, Liu J (2015) Overexpression of Rab5a promotes hepatocellular carcinoma cell proliferation and invasion via FAK signaling pathway. Tumour Biol 6:6
127. Miyazaki T, Kato H, Nakajima M, Sohda M, Fukai Y, Masuda N, Manda R, Fukuchi M, Tsukada K, Kuwano H (2003) FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 89:140–145
128. Hiwatashi K, Tamiya T, Hasegawa E, Fukaya T, Hashimoto M, Kakoi K, Kashiwagi I, Kimura A, Inoue N, Morita R, Yasukawa H, Yoshimura A (2011) Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction. Cancer Lett 308:172–180
129. Zhang S, Guo D, Jiang L, Zhang Q, Qiu X, Wang E (2008) SOCS3 inhibiting migration of A549 cells correlates with PYK2 signaling in vitro. BMC Cancer 8:150
130. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059–20063
131. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809
132. Ludyga N, Anastasov N, Gonzalez-Vasconcellos I, Ram M, Hofler H, Aubele M (2011) Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer. Mol BioSyst 7:1603–1612
133. Gao Y, Cimica V, Reich NC (2012) Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. J Biol Chem 287:20904–20912
134. Barclay JL, Anderson ST, Waters MJ, Curlewis JD (2009) SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL. Int J Cancer 124:1756–1766
135. Rossa C Jr, Sommer G, Spolidorio LC, Rosenzweig SA, Watson DK, Kirkwood KL (2012) Loss of expression and function of SOCS3 is an early event in HNSCC: altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. PLoS One 7:e45197
136. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517
137. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206:1457–1464
138. Siddiqui RA, Harvey KA, Xu Z, Bammerlin EM, Walker C, Altenburg JD (2011) Docosahexaenoic acid: a natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects. BioFactors 37:399–412
139. Berger H, Vegran F, Chikh M, Gilardi F, Ladoire S, Bugaut H, Mignot G, Chalmin F, Bruchard M, Derangere V, Chevriaux A, Rebe C, Ryffel B, Pot C, Hichami A, Desvergne B, Ghiringhelli F, Apetoh L (2013) SOCS3 transactivation by PPARgamma prevents IL-17-driven cancer growth. Cancer Res. doi:10.1158/0008-5472.CAN-12-4018
140. Inagaki-Ohara K, Mayuzumi H, Kato S, Minokoshi Y, Otsubo T, Kawamura YI, Dohi T, Matsuzaki G, Yoshimura A (2012) Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice. Oncogene. doi:10.1038/onc.2012.540
141. Gibadulinova A, Oveckova I, Parkkila S, Pastorekova S, Pastorek J (2008) Key promoter elements involved in transcriptional activation of the cancer-related gene coding for S100P calcium-binding protein. Oncol Rep 20:391–396
142. Cantwell CA, Sterneck E, Johnson PF (1998) Interleukin-6-specific activation of the C/EBPdelta gene in hepatocytes is mediated by Stat3 and Sp1. Mol Cell Biol 18:2108–2117
143. Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F (2000) SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. J Biol Chem 275:12848–12856
144. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M (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
145. Hortner M, Nielsch U, Mayr LM, Johnston JA, Heinrich PC, Haan S (2002) Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction. J Immunol 169:1219–1227
146. De Souza D, Fabri LJ, Nash A, Hilton DJ, Nicola NA, Baca M (2002) SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 41:9229–9236
147. El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, Smith AM, Rutschman R, Kaushal D, Shen Y, Suda T, Donnelly RP, Myers MG Jr, Alexander W, Vignali DA, Watowich SS, Ernst M, Hilton DJ, Murray PJ (2006) General nature of the STAT3-activated anti-inflammatory response. J Immunol 177:7880–7888
148. Niemand C, Nimmesgern A, Haan S, Fischer P, Schaper F, Rossaint R, Heinrich PC, Müller-Newen G (2003) Activation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3. J Immunol 170:3263–3272
149. Matsumura Y, Kobayashi T, Ichiyama K, Yoshida R, Hashimoto M, Takimoto T, Tanaka K, Chinen T, Shichita T, Wyss-Coray T, Sato K, Yoshimura A (2007) Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J Immunol 179:2170–2179
150. Fletcher TC, DiGiandomenico A, Hawiger J (2010) Extended anti-inflammatory action of a degradation-resistant mutant of cell-penetrating suppressor of cytokine signaling 3. J Biol Chem 285:18727–18736
151. Jo D, Liu D, Yao S, Collins RD, Hawiger J (2005) Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med 11:892–898
152. Lui PY, Jin DY, Stevenson NJ (2015) MicroRNA: master controllers of intracellular signaling pathways. Cell Mol Life Sci 72:3531–3542
153. Yoshikawa T, Takata A, Otsuka M, Kishikawa T, Kojima K, Yoshida H, Koike K (2012) Silencing of microRNA-122 enhances interferon-alpha signaling in the liver through regulating SOCS3 promoter methylation. Sci Rep 2:637
154. Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, Croce L, La Mura V, Moschella F, Masutti F, Torella R, Tiribelli C, Iolascon A (2007) Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy. Hepatology 46:1009–1015
155. El-Saadany S, Ziada DH, El Bassat H, Farrag W, El-Serogy H, Eid M, Abdallah M, Ghazy M, Salem HA (2013) The role of hepatic expression of STAT1, SOCS3 and PIAS1 in the response of chronic hepatitis C patients to therapy. Can J Gastroenterol 27:e13–e17
156. Collins AS, McCoy CE, Lloyd AT, O’Farrelly C, Stevenson NJ (2013) miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling. PLoS One 8:e69090
157. Lin YC, Lin CK, Tsai YH, Weng HH, Li YC, You L, Chen JK, Jablons DM, Yang CT (2010) Adenovirus-mediated SOCS3 gene transfer inhibits the growth and enhances the radiosensitivity of human non-small cell lung cancer cells. Oncol Rep 24:1605–1612
158. Cui Q, Jiang W, Wang Y, Lv C, Luo J, Zhang W, Lin F, Yin Y, Cai R, Wei P, Qian C (2008) Transfer of suppressor of cytokine signaling 3 by an oncolytic adenovirus induces potential antitumor activities in hepatocellular carcinoma. Hepatology 47:105–112
159. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A (2013) SOCS, inflammation, and cancer. JAKSTAT 2:e24053
160. Shouda T, Hiraoka K, Komiya S, Hamada T, Zenmyo M, Iwasaki H, Isayama T, Fukushima N, Nagata K, Yoshimura A (2006) Suppression of IL-6 production and proliferation by blocking STAT3 activation in malignant soft tissue tumor cells. Cancer Lett 231:176–184
161. Liang P, Cheng SH, Cheng CK, Lau KM, Lin SY, Chow EY, Chan NP, Ip RK, Wong RS, Ng MH (2013) Platelet factor 4 induces cell apoptosis by inhibition of STAT3 via up-regulation of SOCS3 expression in multiple myeloma. Haematologica 98:288–295
162. Ozaki A, Seki Y, Fukushima A, Kubo M (2005) The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J Immunol 175:5489–5497
163. Uto-Konomi A, Miyauchi K, Ozaki N, Motomura Y, Suzuki Y, Yoshimura A, Suzuki S, Cua D, Kubo M (2012) Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines. PLoS One 7:e40343
164. Bostjancic E, Glavac D (2008) Importance of microRNAs in skin morphogenesis and diseases. Acta Dermatovenerol Alp Panonica Adriat 17:95–102