SOCS3, a major regulator of infection and inflammation

Frontiers in Immunology

Volumn 5, Issue FEB, 2014, Pages

  Carow, Berit ^a   Rottenberg, Martin E ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

Author keywords

Autoimmunity; Cytokine; IL 6; Infection; JAK; SOCS; STAT; STAT3

Indexed keywords

CD33 ANTIGEN; CILIARY NEUROTROPHIC FACTOR; DIOXYGENASE; EPIDERMAL GROWTH FACTOR RECEPTOR; GLYCOPROTEIN GP 130; GRANULOCYTE COLONY STIMULATING FACTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOLEAMINE; INSULIN; INSULIN RECEPTOR SUBSTRATE 1; INSULIN RECEPTOR SUBSTRATE 2; INTERLEUKIN 11; INTERLEUKIN 12; INTERLEUKIN 12 RECEPTOR BETA2; INTERLEUKIN 23 RECEPTOR; INTERLEUKIN 27; INTERLEUKIN 6; JANUS KINASE; LEPTIN; LEPTIN RECEPTOR; LEUKEMIA INHIBITORY FACTOR; ONCOSTATIN M; SIALIC ACID BINDING IMMUNOGLOBULIN LIKE LECTIN; STAT1 PROTEIN; STAT3 PROTEIN; STAT4 PROTEIN; SUPPRESSOR OF CYTOKINE SIGNALING 3; TRANSFORMING GROWTH FACTOR; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 6; UNINDEXED DRUG;

ALLERGIC ENCEPHALOMYELITIS; BACTERIAL INFECTION; CELL POPULATION; CLINICAL TRIAL (TOPIC); ENZYME ACTIVITY; HEMATOPOIESIS; HUMAN; IMMUNE RESPONSE; INFECTION; INFLAMMATION; NEURAL STEM CELL; NONHUMAN; PARASITOSIS; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; PSORIASIS; REVIEW; SIGNAL TRANSDUCTION; THROMBOSIS; UBIQUITINATION; VIRUS INFECTION; WEIGHT GAIN;

EID: 84895551972     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00058     Document Type: Review

References (166)

1. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science (1994) 264:1415-21. doi:10.1126/science.8197455.
2. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol (2002) 3:651-62. doi:10.1038/nrm909.
3. Ihle JN. STATs: signal transducers and activators of transcription. Cell (1996) 84:331-4. doi:10.1016/S0092-8674(00)81277-5.
4. Levy DE, Marie IJ. STATus report on tetramers. Immunity (2012) 36:553-5. doi:10.1016/j.immuni.2012.04.003.
5. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol (2003) 3:900-11. doi:10.1038/nri1226.
6. Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci (2008) 13:4925-32. doi:10.2741/3051.
7. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A (1998) 95:10626-31. doi:10.1073/pnas.95.18.10626.
8. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol (2005) 5:593-605. doi:10.1038/nri1667.
9. Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci U S A (1998) 95:14395-9. doi:10.1073/pnas.95.24.14395.
10. Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola NA, et al. Gigantism in mice lacking suppressor of cytokine signalling-2. Nature (2000) 405:1069-73. doi:10.1038/35016611.
11. Marine JC, Mckay C, Wang D, Topham DJ, Parganas E, Nakajima H, et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell (1999) 98:617-27. doi:10.1016/S0092-8674(00)80049-5.
12. Roberts AW, Robb L, Rakar S, Hartley L, Cluse L, Nicola NA, et al. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc Natl Acad Sci U S A (2001) 98:9324-9. doi:10.1073/pnas.161271798.
13. Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity (2012) 36:503-14. doi:10.1016/j.immuni.2012.03.013.
14. Lee JE, Yang YM, Liang FX, Gough DJ, Levy DE, Sehgal PB. Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol (2012) 302:C804-20. doi:10.1152/ajpcell.00379.2011.
15. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science (2009) 323:793-7. doi:10.1126/science.1164551.
16. Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol (2008) 18:545-51. doi:10.1016/j.tcb.2008.08.008.
17. Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett (2012) 318:124-34. doi:10.1016/j.canlet.2012.01.011.
18. Leaman DW, Pisharody S, Flickinger TW, Commane MA, Schlessinger J, Kerr IM, et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol Cell Biol (1996) 16:369-75.
19. Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR. STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A (2013) 110:16975-80. doi:10.1073/pnas.1315862110.
20. Escary JL, Perreau J, Dumenil D, Ezine S, Brulet P. Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation. Nature (1993) 363:361-4. doi:10.1038/363361a0.
21. Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci U S A (1996) 93:407-11. doi:10.1073/pnas.93.1.407.
22. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol (2007) 7:454-65. doi:10.1038/nri2093.
23. Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F. SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. J Biol Chem (2000) 275:12848-56. doi:10.1074/jbc.275.17.12848.
24. Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, et al. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem (2003) 278:661-71. doi:10.1074/jbc.M210552200.
25. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, et al. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A (2000) 97:6493-8. doi:10.1073/pnas.100135197.
26. Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest (2008) 118:1727-38. doi:10.1172/JCI34944.
27. Brender C, Tannahill GM, Jenkins BJ, Fletcher J, Columbus R, Saris CJ, et al. Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27. Blood (2007) 110:2528-36. doi:10.1182/blood-2006-08-041541.
28. Magrangeas F, Boisteau O, Denis S, Jacques Y, Minvielle S. Negative cross-talk between interleukin-3 and interleukin-11 is mediated by suppressor of cytokine signalling-3 (SOCS-3). Biochem J (2001) 353:223-30. doi:10.1042/0264-6021:3530223.
29. Hamanaka I, Saito Y, Yasukawa H, Kishimoto I, Kuwahara K, Miyamoto Y, et al. Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 is involved in gp130 resistance in cardiovascular system in rat treated with cardiotrophin-1 in vivo. Circ Res (2001) 88:727-32. doi:10.1161/hh0701.088512.
30. Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN, et al. SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol (2003) 4:546-50. doi:10.1038/ni932.
31. Auernhammer CJ, Chesnokova V, Bousquet C, Melmed S. Pituitary corticotroph SOCS-3: novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion. Mol Endocrinol (1998) 12:954-61. doi:10.1210/me.12.7.954.
32. Hortner M, Nielsch U, Mayr LM, Johnston JA, Heinrich PC, Haan S. Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction. J Immunol (2002) 169:1219-27.
33. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A (2006) 103:8137-42. doi:10.1073/pnas.0600666103.
34. Hortner M, Nielsch U, Mayr LM, Heinrich PC, Haan S. A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. Eur J Biochem (2002) 269:2516-26. doi:10.1046/j.1432-1033.2002.02916.x.
35. Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem (2000) 275:40649-57. doi:10.1074/jbc.M007577200.
36. Eyckerman S, Broekaert D, Verhee A, Vandekerckhove J, Tavernier J. Identification of the Y985 and Y1077 motifs as SOCS3 recruitment sites in the murine leptin receptor. FEBS Lett (2000) 486:33-7. doi:10.1016/S0014-5793(00)02205-5.
37. Yamamoto K, Yamaguchi M, Miyasaka N, Miura O. 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 (2003) 310:1188-93. doi:10.1016/j.bbrc.2003.09.140.
38. Orabona C, Pallotta MT, Volpi C, Fallarino F, Vacca C, Bianchi R, et al. SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc Natl Acad Sci U S A (2008) 105:20828-33. doi:10.1073/pnas.0810278105.
39. Orr SJ, Morgan NM, Elliott J, Burrows JF, Scott CJ, Mcvicar DW, et al. CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover. Blood (2007) 109:1061-8. doi:10.1182/blood-2006-05-023556.
40. Orr SJ, Morgan NM, Buick RJ, Boyd CR, Elliott J, Burrows JF, et al. SOCS3 targets Siglec 7 for proteasomal degradation and blocks Siglec 7-mediated responses. J Biol Chem (2007) 282:3418-22. doi:10.1074/jbc.C600216200.
41. Frobose H, Ronn SG, Heding PE, Mendoza H, Cohen P, Mandrup-Poulsen T, et al. Suppressor of cytokine signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Mol Endocrinol (2006) 20:1587-96. doi:10.1210/me.2005-0301.
42. Nair S, Pandey AD, Mukhopadhyay S. 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 (2011) 186:5413-24. doi:10.4049/jimmunol.1000773.
43. Zhang Z, Liu Q, Che Y, Yuan X, Dai L, Zeng B, et al. Antigen presentation by dendritic cells in tumors is disrupted by altered metabolism that involves pyruvate kinase M2 and its interaction with SOCS3. Cancer Res (2010) 70:89-98. doi:10.1158/0008-5472.CAN-09-2970.
44. Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem (2002) 277:42394-8. doi:10.1074/jbc.C200444200.
45. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, et al. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J (1995) 14:2816-26.
46. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature (1997) 387:921-4. doi:10.1038/43213.
47. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, et al. Structure and function of a new STAT-induced STAT inhibitor. Nature (1997) 387:924-9. doi:10.1038/43219.
48. Minamoto S, Ikegame K, Ueno K, Narazaki M, Naka T, Yamamoto H, et al. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem Biophys Res Commun (1997) 237:79-83. doi:10.1006/bbrc.1997.7080.
49. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al. A family of cytokine-inducible inhibitors of signalling. Nature (1997) 387:917-21. doi:10.1038/43206.
50. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci U S A (1998) 95:114-9. doi:10.1073/pnas.95.1.114.
51. Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, et al. 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 U S A (1999) 96:2071-6. doi:10.1073/pnas.96.5.2071.
52. Babon JJ, Sabo JK, Zhang JG, Nicola NA, Norton RS. The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression. J Mol Biol (2009) 387:162-74. doi:10.1016/j.jmb.2009.01.024.
53. Fletcher TC, DiGiandomenico A, Hawiger J. Extended anti-inflammatory action of a degradation-resistant mutant of cell-penetrating suppressor of cytokine signaling 3. J Biol Chem (2010) 285:18727-36. doi:10.1074/jbc.M109.095216.
54. Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, et al. Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. Genes Cells (1999) 4:339-51. doi:10.1046/j.1365-2443.1999.00263.x.
55. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J (1999) 18:1309-20. doi:10.1093/emboj/18.5.1309.
56. Babon JJ, Kershaw NJ, Murphy JM, Varghese LN, Laktyushin A, Young SN, et al. Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity (2012) 36:239-50. doi:10.1016/j.immuni.2011.12.015.
57. Bergamin E, Wu J, Hubbard SR. Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3. Structure (2006) 14:1285-92. doi:10.1016/j.str.2006.06.011.
58. Kershaw NJ, Murphy JM, Liau NP, Varghese LN, Laktyushin A, Whitlock EL, et al. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol (2013) 20:469-76. doi:10.1038/nsmb.2519.
59. Babon JJ, Mcmanus EJ, Yao S, Desouza DP, Mielke LA, Sprigg NS, et al. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol Cell (2006) 22:205-16. doi:10.1016/j.molcel.2006.03.024.
60. Irandoust MI, Aarts LH, Roovers O, Gits J, Erkeland SJ, Touw IP. Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. EMBO J (2007) 26:1782-93. doi:10.1038/sj.emboj.7601709.
61. Boyle K, Egan P, Rakar S, Willson TA, Wicks IP, Metcalf D, et al. The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo. Blood (2007) 110:1466-74. doi:10.1182/blood-2007-03-079178.
62. Nguyen-Jackson H, Panopoulos AD, Zhang H, Li HS, Watowich SS. STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction. Blood (2010) 115:3354-63. doi:10.1182/blood-2009-08-240317.
63. Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol (2003) 4:540-5. doi:10.1038/ni931.
64. Robb L, Boyle K, Rakar S, Hartley L, Lochland J, Roberts AW, et al. Genetic reduction of embryonic leukemia-inhibitory factor production rescues placentation in SOCS3-null embryos but does not prevent inflammatory disease. Proc Natl Acad Sci U S A (2005) 102:16333-8. doi:10.1073/pnas.0508023102.
65. Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata T, et al. Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3-and SHP2-mediated signals in immune responses. Immunity (2000) 12:95-105. doi:10.1016/S1074-7613(00)80162-4.
66. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med (2004) 10:734-8. doi:10.1038/nm1072.
67. Palanivel R, Fullerton MD, Galic S, Honeyman J, Hewitt KA, Jorgensen SB, et al. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance. Diabetologia (2012) 55:3083-93. doi:10.1007/s00125-012-2665-3.
68. Silver JS, Stumhofer JS, Passos S, Ernst M, Hunter CA. IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. J Immunol (2011) 187:350-60. doi:10.4049/jimmunol.1004144.
69. Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med (2005) 11:845-52. doi:10.1038/nm1282.
70. Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med (2002) 8:1089-97. doi:10.1038/nm763.
71. Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol (2007) 19:695-702. doi:10.1093/intimm/dxm045.
72. Sodenkamp J, Behrends J, Forster I, Muller W, Ehlers S, Holscher C. gp130 on macrophages/granulocytes modulates inflammation during experimental tuberculosis. Eur J Cell Biol (2011) 90:505-14. doi:10.1016/j.ejcb.2010.10.010.
73. Croom HA, Izon DJ, Chong MM, Curtis DJ, Roberts AW, Kay TW, et al. Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3. Mol Immunol (2008) 45:2888-96. doi:10.1016/j.molimm.2008.01.024.
74. Carow B, Reuschl AK, Gavier-Widen D, Jenkins BJ, Ernst M, Yoshimura A, et al. Critical and independent role for SOCS3 in either myeloid or T cells in resistance to Mycobacterium tuberculosis. PLoS Pathog (2013) 9:e1003442. doi:10.1371/journal.ppat.1003442.
75. Hill GR, Kuns RD, Raffelt NC, Don AL, Olver SD, Markey KA, et al. SOCS3 regulates graft-versus-host disease. Blood (2010) 116:287-96. doi:10.1182/blood-2009-12-259598.
76. Moriwaki A, Inoue H, Nakano T, Matsunaga Y, Matsuno Y, Matsumoto T, et al. T cell treatment with small interfering RNA for suppressor of cytokine signaling 3 modulates allergic airway responses in a murine model of asthma. Am J Respir Cell Mol Biol (2011) 44:448-55. doi:10.1165/rcmb.2009-0051OC.
77. Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, et al. 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 (2006) 203:1021-31. doi:10.1084/jem.20052333.
78. Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O, et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med (2009) 206:2067-77. doi:10.1084/jem.20090545.
79. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell (2011) 144:601-13. doi:10.1016/j.cell.2011.01.011.
80. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol (2003) 4:551-6. doi:10.1038/ni938.
81. Matsumura Y, Kobayashi T, Ichiyama K, Yoshida R, Hashimoto M, Takimoto T, et al. Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J Immunol (2007) 179:2170-9.
82. Yan C, Ward PA, Wang X, Gao H. Myeloid depletion of SOCS3 enhances LPS-induced acute lung injury through CCAAT/enhancer binding protein delta pathway. FASEB J (2013) 27:2967-76. doi:10.1096/fj.12-225797.
83. Qin H, Holdbrooks AT, Liu Y, Reynolds SL, Yanagisawa LL, Benveniste EN. SOCS3 deficiency promotes M1 macrophage polarization and inflammation. J Immunol (2012) 189:3439-48. doi:10.4049/jimmunol.1201168.
84. Whitmarsh RJ, Gray CM, Gregg B, Christian DA, May MJ, Murray PJ, et al. A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host Microbe (2011) 10:224-36. doi:10.1016/j.chom.2011.07.009.
85. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med (2004) 10:739-43. doi:10.1038/nm1071.
86. Emery B, Butzkueven H, Snell C, Binder M, Kilpatrick TJ. Oligodendrocytes exhibit selective expression of suppressor of cytokine signaling genes and signal transducer and activator of transcription 1 independent inhibition of interferon-gamma-induced toxicity in response to leukemia inhibitory factor. Neuroscience (2006) 137:463-72. doi:10.1016/j.neuroscience.2005.09.022.
87. Emery B, Cate HS, Marriott M, Merson T, Binder MD, Snell C, et al. Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination. Proc Natl Acad Sci U S A (2006) 103:7859-64. doi:10.1073/pnas.0602574103.
88. Croker BA, Metcalf D, Robb L, Wei W, Mifsud S, Dirago L, et al. SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity (2004) 20:153-65. doi:10.1016/S1074-7613(04)00022-6.
89. Croker BA, Kiu H, Pellegrini M, Toe J, Preston S, Metcalf D, et al. IL-6 promotes acute and chronic inflammatory disease in the absence of SOCS3. Immunol Cell Biol (2012) 90:124-9. doi:10.1038/icb.2011.29.
90. Wong PK, Egan PJ, Croker BA, O'Donnell K, Sims NA, Drake S, et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest (2006) 116:1571-81. doi:10.1172/JCI25660.
91. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, et al. SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med (2003) 9:1047-54. doi:10.1038/nm896.
92. Ozaki A, Seki Y, Fukushima A, Kubo M. The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J Immunol (2005) 175:5489-97.
93. Romain M, Taleb S, Dalloz M, Ponnuswamy P, Esposito B, Perez N, et al. Overexpression of SOCS3 in T lymphocytes leads to impaired interleukin-17 production and severe aortic aneurysm formation in mice-brief report. Arterioscler Thromb Vasc Biol (2013) 33:581-4. doi:10.1161/ATVBAHA.112.300516.
94. Nakaya M, Hamano S, Kawasumi M, Yoshida H, Yoshimura A, Kobayashi T. Aberrant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations. Int Immunol (2011) 23:195-202. doi:10.1093/intimm/dxq472.
95. Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, et al. Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene (2006) 25:2520-30. doi:10.1038/sj.onc.1209281.
96. Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, et al. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest (2001) 108:1781-8. doi:10.1172/JCI200113568.
97. Jo D, Liu D, Yao S, Collins RD, Hawiger J. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med (2005) 11:892-8. doi:10.1038/nm1269.
98. Qin H, Yeh WI, De Sarno P, Holdbrooks AT, Liu Y, Muldowney MT, et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci U S A (2012) 109:5004-9. doi:10.1073/pnas.1117218109.
99. Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C, Kanamoto M, et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity (2008) 29:628-36. doi:10.1016/j.immuni.2008.07.018.
100. Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat Immunol (2003) 4:1169-76. doi:10.1038/ni1012.
101. Wormald S, Zhang JG, Krebs DL, Mielke LA, Silver J, Alexander WS, et al. The comparative roles of suppressor of cytokine signaling-1 and-3 in the inhibition and desensitization of cytokine signaling. J Biol Chem (2006) 281:11135-43. doi:10.1074/jbc.M509595200.
102. Braun DA, Fribourg M, Sealfon SC. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem (2013) 288:2986-93. doi:10.1074/jbc.M112.386573.
103. Liu X, Zhang Y, Yu Y, Yang X, Cao X. SOCS3 promotes TLR4 response in macrophages by feedback inhibiting TGF-beta1/Smad3 signaling. Mol Immunol (2008) 45:1405-13. doi:10.1016/j.molimm.2007.08.018.
104. Spence S, Fitzsimons A, Boyd CR, Kessler J, Fitzgerald D, Elliott J, et al. Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization. Immunity (2013) 38:66-78. doi:10.1016/j.immuni.2012.09.013.
105. Liu Y, Stewart KN, Bishop E, Marek CJ, Kluth DC, Rees AJ, et al. Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol (2008) 180:6270-8.
106. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science (1999) 284:770-6. doi:10.1126/science.284.5415.770.
107. Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res (2010) 70:4840-9. doi:10.1158/0008-5472.CAN-10-0269.
108. Narayana Y, Balaji KN. NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages. J Biol Chem (2008) 283:12501-11. doi:10.1074/jbc.M709960200.
109. Kimura A, Kinjyo I, Matsumura Y, Mori H, Mashima R, Harada M, et al. SOCS3 is a physiological negative regulator for granulopoiesis and granulocyte colony-stimulating factor receptor signaling. J Biol Chem (2004) 279:6905-10. doi:10.1074/jbc.C300496200.
110. Croker BA, Mielke LA, Wormald S, Metcalf D, Kiu H, Alexander WS, et al. Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation. Exp Hematol (2008) 36:786-98. doi:10.1016/j.exphem.2008.02.008.
111. Orabona C, Belladonna ML, Vacca C, Bianchi R, Fallarino F, Volpi C, et al. Cutting edge: silencing suppressor of cytokine signaling 3 expression in dendritic cells turns CD28-Ig from immune adjuvant to suppressant. J Immunol (2005) 174:6582-6.
112. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem (2003) 278:13740-6. doi:10.1074/jbc.M210689200.
113. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E. SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem (2000) 275:15985-91. doi:10.1074/jbc.275.21.15985.
114. Shi H, Tzameli I, Bjorbaek C, Flier JS. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem (2004) 279:34733-40. doi:10.1074/jbc.M403886200.
115. Lovibond AC, Haque SJ, Chambers TJ, Fox SW. TGF-beta-induced SOCS3 expression augments TNF-alpha-induced osteoclast formation. Biochem Biophys Res Commun (2003) 309:762-7. doi:10.1016/j.bbrc.2003.08.068.
116. Caruso R, Stolfi C, Sarra M, Rizzo A, Fantini MC, Pallone F, et al. Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase-dependent induction of Socs-3. Blood (2009) 113:3512-9. doi:10.1182/blood-2008-08-172767.
117. Schneider R, Yaneva T, Beauseigle D, El-Khoury L, Arbour N. IL-27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells. Eur J Immunol (2011) 41:47-59. doi:10.1002/eji.201040804.
118. Owaki T, Asakawa M, Kamiya S, Takeda K, Fukai F, Mizuguchi J, et al. IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3. J Immunol (2006) 176:2773-80.
119. Egwuagu CE, Yu CR, Zhang M, Mahdi RM, Kim SJ, Gery I. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J Immunol (2002) 168:3181-7.
120. Horiuchi Y, Bae SJ, Katayama I. Overexpression of the suppressor of cytokine signalling 3 (SOCS3) in severe atopic dermatitis. Clin Exp Dermatol (2006) 31:100-4. doi:10.1111/j.1365-2230.2005.01979.x.
121. Ekelund E, Saaf A, Tengvall-Linder M, Melen E, Link J, Barker J, et al. Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis. Am J Hum Genet (2006) 78:1060-5. doi:10.1086/504272.
122. Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, et al. Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads. J Immunol (2008) 180:3746-56.
123. Qin H, Wang L, Feng T, Elson CO, Niyongere SA, Lee SJ, et al. TGF-beta promotes Th17 cell development through inhibition of SOCS3. J Immunol (2009) 183:97-105. doi:10.4049/jimmunol.0801986.
124. Ivanov II, Mckenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammaT directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell (2006) 126:1121-33. doi:10.1016/j.cell.2006.07.035.
125. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity (2006) 24:179-89. doi:10.1016/j.immuni.2006.01.001.
126. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature (2008) 452:773-6. doi:10.1038/nature06764.
127. Gistera A, Robertson AK, Andersson J, Ketelhuth DF, Ovchinnikova O, Nilsson SK, et al. Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway. Sci Transl Med (2013) 5:196ra100. doi:10.1126/scitranslmed.3006133.
128. Cao W, Yang Y, Wang Z, Liu A, Fang L, Wu F, et al. Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity (2011) 35:273-84. doi:10.1016/j.immuni.2011.06.011.
129. Li Y, Chu N, Rostami A, Zhang GX. Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. J Immunol (2006) 177:1679-88.
130. Carow B, Rottenberg ME. "Suppressor of cytokine signalling" molecules in infection and inflammation. In: Mahin K, editor. Inflammation, Chronic Diseases and Cancer-Cell and Molecular Biology, Immunology and Clinical Bases. InTech (2012). doi:10.5772/25986.
131. Babon JJ, Nicola NA. The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors (2012) 30:207-19. doi:10.3109/08977194.2012.687375.
132. Yokota S, Yokosawa N, Okabayashi T, Suzutani T, Fujii N. Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 confers efficient viral replication. Virology (2005) 338:173-81. doi:10.1016/j.virol.2005.04.028.
133. Hashimoto K, Ishibashi K, Ishioka K, Zhao D, Sato M, Ohara S, et al. RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules. Virology (2009) 391:162-70. doi:10.1016/j.virol.2009.06.026.
134. Bixler SL, Sandler NG, Douek DC, Mattapallil JJ. Suppressed Th17 levels correlate with elevated PIAS3, SHP2, and SOCS3 expression in CD4 T cells during acute simian immunodeficiency virus infection. J Virol (2013) 87:7093-101. doi:10.1128/JVI.00600-13.
135. Akhtar LN, Qin H, Muldowney MT, Yanagisawa LL, Kutsch O, Clements JE, et al. Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. J Immunol (2010) 185:2393-404. doi:10.4049/jimmunol.0903563.
136. Kim KA, Lin W, Tai AW, Shao RX, Weinberg E, De Sa Borges CB, et al. Hepatic SOCS3 expression is strongly associated with non-response to therapy and race in HCV and HCV/HIV infection. J Hepatol (2009) 50:705-11. doi:10.1016/j.jhep.2008.12.021.
137. Michaud F, Coulombe F, Gaudreault E, Paquet-Bouchard C, Rola-Pleszczynski M, Gosselin J. Epstein-Barr virus interferes with the amplification of IFNalpha secretion by activating suppressor of cytokine signaling 3 in primary human monocytes. PLoS One (2010) 5:e11908. doi:10.1371/journal.pone.0011908.
138. Kim K, Kim KH, Cheong J. Hepatitis B virus X protein impairs hepatic insulin signaling through degradation of IRS1 and induction of SOCS3. PLoS One (2010) 5:e8649. doi:10.1371/journal.pone.0008649.
139. Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol (2004) 165:1499-508. doi:10.1016/S0002-9440(10)63408-6.
140. Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, et al. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy. Hepatology (2007) 46:1009-15. doi:10.1002/hep.21782.
141. Persico M, Capasso M, Russo R, Persico E, Croce L, Tiribelli C, et al. Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C. Gut (2008) 57:507-15. doi:10.1136/gut.2007.129478.
142. Funaoka Y, Sakamoto N, Suda G, Itsui Y, Nakagawa M, Kakinuma S, et al. Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91. J Virol (2011) 85:5986-94. doi:10.1128/JVI.02583-10.
143. Pothlichet J, Chignard M, Si-Tahar M. Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway. J Immunol (2008) 180:2034-8.
144. Pauli EK, Schmolke M, Wolff T, Viemann D, Roth J, Bode JG, et al. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog (2008) 4:e1000196. doi:10.1371/journal.ppat.1000196.
145. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity (2011) 35:792-805. doi:10.1016/j.immuni.2011.09.017.
146. Masood KI, Rottenberg ME, Salahuddin N, Irfan M, Rao N, Carow B, et al. 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 (2013) 13:13. doi:10.1186/1471-2334-13-13.
147. Yoshikawa T, Takata A, Otsuka M, Kishikawa T, Kojima K, Yoshida H, et al. Silencing of microRNA-122 enhances interferon-alpha signaling in the liver through regulating SOCS3 promoter methylation. Sci Rep (2012) 2:637. doi:10.1038/srep00637.
148. Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, et al. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. J Exp Med (2009) 206:2747-60. doi:10.1084/jem.20091703.
149. Carow B, Ye X, Gavier-Widen D, Bhuju S, Oehlmann W, Singh M, et al. Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-{gamma} (IFN-{gamma})-dependent manner. J Biol Chem (2011) 286:26873-87. doi:10.1074/jbc.M111.238287.
150. Sodenkamp J, Waetzig GH, Scheller J, Seegert D, Grotzinger J, Rose-John S, et al. Therapeutic targeting of interleukin-6 trans-signaling does not affect the outcome of experimental tuberculosis. Immunobiology (2012) 217:996-1004. doi:10.1016/j.imbio.2012.01.015.
151. Saunders BM, Frank AA, Orme IM, Cooper AM. Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect Immun (2000) 68:3322-6. doi:10.1128/IAI.68.6.3322-3326.2000.
152. Miao T, Wu D, Zhang Y, Bo X, Subang MC, Wang P, et al. Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons. J Neurosci (2006) 26:9512-9. doi:10.1523/JNEUROSCI.2160-06.2006.
153. Mckay BR, Ogborn DI, Baker JM, Toth KG, Tarnopolsky MA, Parise G. Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction. Am J Physiol Cell Physiol (2013) 304:C717-28. doi:10.1152/ajpcell.00305.2012.
154. Jiang C, Kim JH, Li F, Qu A, Gavrilova O, Shah YM, et al. Hypoxia-inducible factor 1alpha regulates a SOCS3-STAT3-adiponectin signal transduction pathway in adipocytes. J Biol Chem (2013) 288:3844-57. doi:10.1074/jbc.M112.426338.
155. Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, et al. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med (2001) 193:471-81. doi:10.1084/jem.193.4.471.
156. Ortiz-Munoz G, Martin-Ventura JL, Hernandez-Vargas P, Mallavia B, Lopez-Parra V, Lopez-Franco O, et al. Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis. Arterioscler Thromb Vasc Biol (2009) 29:525-31. doi:10.1161/ATVBAHA.108.173781.
157. Wunderlich CM, Hovelmeyer N, Wunderlich FT. Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAKSTAT (2013) 2:e23878. doi:10.4161/jkst.23878.
158. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature (1998) 395:763-70. doi:10.1038/27376.
159. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell (1998) 1:619-25. doi:10.1016/S1097-2765(00)80062-3.
160. Balthasar N, Coppari R, Mcminn J, Liu SM, Lee CE, Tang V, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron (2004) 42:983-91. doi:10.1016/j.neuron.2004.06.004.
161. Oba T, Yasukawa H, Hoshijima M, Sasaki K, Futamata N, Fukui D, et al. Cardiac-specific deletion of SOCS-3 prevents development of left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol (2012) 59:838-52. doi:10.1016/j.jacc.2011.10.887.
162. Veenbergen S, Bennink MB, de Hooge AS, Arntz OJ, Smeets RL, van den Berg WB, et al. Splenic suppressor of cytokine signaling 3 transgene expression affects T cell responses and prevents development of collagen-induced arthritis. Arthritis Rheum (2008) 58:3742-52. doi:10.1002/art.24072.
163. Gu H, Liu L, Ma S, Liu Y, Ren Y, Zhai L, et al. Inhibition of SOCS-3 in adipocytes of rats with diet-induced obesity increases leptin-mediated fatty acid oxidation. Endocrine (2009) 36:546-54. doi:10.1007/s12020-009-9253-4.
164. Wang X, Crowe PJ, Goldstein D, Yang JL. STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (review). Int J Oncol (2012) 41:1181-91. doi:10.3892/ijo.2012.1568.
165. Yu H, Jove R. The STATs of cancer-new molecular targets come of age. Nat Rev Cancer (2004) 4:97-105. doi:10.1038/nrc1275.
166. Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA. Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res (2006) 66:3162-8. doi:10.1158/0008-5472.CAN-05-3757.