{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:51:07Z","timestamp":1760298667118},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are multifunctional cytokines that regulate immune responses, cell proliferation, and tumour development and progression, which frequently have functionally opposing roles. The cellular responses to both cytokines are activated via the Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) pathway. During the past 10 years, the crosstalk mechanism between the IFN-gamma and IL-6 pathways has been studied widely and several biological hypotheses have been proposed, but the kinetics and detailed crosstalk mechanism remain unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Using established mathematical models and new experimental observations of the crosstalk between the IFN-gamma and IL-6 pathways, we constructed a new crosstalk model that considers three possible crosstalk levels: (1) the competition between STAT1 and STAT3 for common receptor docking sites; (2) the mutual negative regulation between SOCS1 and SOCS3; and (3) the negative regulatory effects of the formation of STAT1\/3 heterodimers. A number of simulations were tested to explore the consequences of cross-regulation between the two pathways. The simulation results agreed well with the experimental data, thereby demonstrating the effectiveness and correctness of the model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>In this study, we developed a crosstalk model of the IFN-gamma and IL-6 pathways to theoretically investigate their cross-regulation mechanism. The simulation experiments showed the importance of the three crosstalk levels between the two pathways. In particular, the unbalanced competition between STAT1 and STAT3 for IFNR and gp130 led to preferential activation of IFN-gamma and IL-6, while at the same time the formation of STAT1\/3 heterodimers enhanced preferential signal transduction by sequestering a fraction of the activated STATs. The model provided a good explanation of the experimental observations and provided insights that may inform further research to facilitate a better understanding of the cross-regulation mechanism between the two pathways.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-14-41","type":"journal-article","created":{"date-parts":[[2013,2,6]],"date-time":"2013-02-06T01:14:14Z","timestamp":1360113254000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Elucidating the crosstalk mechanism between IFN-gamma and IL-6 via mathematical modelling"],"prefix":"10.1186","volume":"14","author":[{"given":"Yun-feng","family":"Qi","sequence":"first","affiliation":[]},{"given":"Yan-xin","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Hong-yan","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Yong-li","family":"Bao","sequence":"additional","affiliation":[]},{"given":"Lu-guo","family":"Sun","sequence":"additional","affiliation":[]},{"given":"Yin","family":"Wu","sequence":"additional","affiliation":[]},{"given":"Chun-lei","family":"Yu","sequence":"additional","affiliation":[]},{"given":"Zhen-bo","family":"Song","sequence":"additional","affiliation":[]},{"given":"Li-hua","family":"Zheng","sequence":"additional","affiliation":[]},{"given":"Ying","family":"Sun","sequence":"additional","affiliation":[]},{"given":"Guan-nan","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Yu-xin","family":"Li","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2013,2,6]]},"reference":[{"issue":"28","key":"5728_CR1","doi-asserted-by":"publisher","first-page":"20059","DOI":"10.1074\/jbc.R700016200","volume":"282","author":"C Schindler","year":"2007","unstructured":"Schindler C, Levy DE, Decker T: JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007,282(28):20059-20063. 10.1074\/jbc.R700016200","journal-title":"J Biol Chem"},{"issue":"Pt 1","key":"5728_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj20030407","volume":"374","author":"PC Heinrich","year":"2003","unstructured":"Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003,374(Pt 1):1-20.","journal-title":"Biochem J"},{"issue":"21","key":"5728_CR3","doi-asserted-by":"publisher","first-page":"2638","DOI":"10.1038\/sj.onc.1203522","volume":"19","author":"K Shuai","year":"2000","unstructured":"Shuai K: Modulation of STAT signaling by STAT-interacting proteins. Oncogene 2000,19(21):2638-2644. 10.1038\/sj.onc.1203522","journal-title":"Oncogene"},{"issue":"2","key":"5728_CR4","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1359-6101(01)00038-7","volume":"13","author":"H Ikeda","year":"2002","unstructured":"Ikeda H, Old LJ, Schreiber RD: The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002,13(2):95-109. 10.1016\/S1359-6101(01)00038-7","journal-title":"Cytokine Growth Factor Rev"},{"issue":"Pt 1","key":"5728_CR5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1042\/bj20031495","volume":"379","author":"S Radaeva","year":"2004","unstructured":"Radaeva S, Jaruga B, Kim WH, Heller T, Liang TJ, Gao B: Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C. Biochem J 2004,379(Pt 1):199-208.","journal-title":"Biochem J"},{"issue":"4","key":"5728_CR6","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.semcdb.2008.06.004","volume":"19","author":"G Regis","year":"2008","unstructured":"Regis G, Pensa S, Boselli D, Novelli F, Poli V: Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol 2008,19(4):351-359. 10.1016\/j.semcdb.2008.06.004","journal-title":"Semin Cell Dev Biol"},{"issue":"1","key":"5728_CR7","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1046\/j.1432-1327.1999.00149.x","volume":"260","author":"M Koster","year":"1999","unstructured":"Koster M, Hauser H: Dynamic redistribution of STAT1 protein in IFN signaling visualized by GFP fusion proteins. Eur J Biochem 1999,260(1):137-144. 10.1046\/j.1432-1327.1999.00149.x","journal-title":"Eur J Biochem"},{"issue":"2","key":"5728_CR8","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1189\/jlb.0603252","volume":"75","author":"K Schroder","year":"2004","unstructured":"Schroder K, Hertzog PJ, Ravasi T, Hume DA: Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004,75(2):163-189.","journal-title":"J Leukoc Biol"},{"issue":"6-7","key":"5728_CR9","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.ejcb.2011.09.010","volume":"91","author":"R Eulenfeld","year":"2011","unstructured":"Eulenfeld R, Dittrich A, Khouri C, Muller PJ, Mutze B, Wolf A, Schaper F: Interleukin-6 signalling: More than Jaks and STATs. Eur J Cell Biol 2011,91(6-7):486-495.","journal-title":"Eur J Cell Biol"},{"issue":"Suppl","key":"5728_CR10","doi-asserted-by":"publisher","first-page":"S121","DOI":"10.1016\/S0092-8674(02)00701-8","volume":"109","author":"JJ O\u2019Shea","year":"2002","unstructured":"O\u2019Shea JJ, Gadina M, Schreiber RD: Cytokine signaling in 2002: new surprises in the Jak\/Stat pathway. Cell 2002,109(Suppl):S121-131.","journal-title":"Cell"},{"issue":"11","key":"5728_CR11","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1038\/nri1226","volume":"3","author":"K Shuai","year":"2003","unstructured":"Shuai K, Liu B: Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 2003,3(11):900-911. 10.1038\/nri1226","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"5728_CR12","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1097\/00024382-200202000-00001","volume":"17","author":"RN Cooney","year":"2002","unstructured":"Cooney RN: Suppressors of cytokine signaling (SOCS): inhibitors of the JAK\/STAT pathway. Shock 2002,17(2):83-90. 10.1097\/00024382-200202000-00001","journal-title":"Shock"},{"issue":"25","key":"5728_CR13","doi-asserted-by":"publisher","first-page":"22086","DOI":"10.1074\/jbc.M102737200","volume":"276","author":"M Brysha","year":"2001","unstructured":"Brysha M, Zhang JG, Bertolino P, Corbin JE, Alexander WS, Nicola NA, Hilton DJ, Starr R: Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo. J Biol Chem 2001,276(25):22086-22089. 10.1074\/jbc.M102737200","journal-title":"J Biol Chem"},{"issue":"3","key":"5728_CR14","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1128\/MCB.19.3.2416","volume":"19","author":"M You","year":"1999","unstructured":"You M, Yu DH, Feng GS: Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak\/STAT pathway. Mol Cell Biol 1999,19(3):2416-2424.","journal-title":"Mol Cell Biol"},{"issue":"Pt 3","key":"5728_CR15","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1042\/bj3350557","volume":"335","author":"F Schaper","year":"1998","unstructured":"Schaper F, Gendo C, Eck M, Schmitz J, Grimm C, Anhuf D, Kerr IM, Heinrich PC: Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. Biochem J 1998,335(Pt 3):557-565.","journal-title":"Biochem J"},{"issue":"16","key":"5728_CR16","doi-asserted-by":"publisher","first-page":"5662","DOI":"10.1128\/MCB.22.16.5662-5668.2002","volume":"22","author":"J ten Hoeve","year":"2002","unstructured":"ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, Shuai K: Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 2002,22(16):5662-5668. 10.1128\/MCB.22.16.5662-5668.2002","journal-title":"Mol Cell Biol"},{"issue":"9","key":"5728_CR17","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nrm909","volume":"3","author":"DE Levy","year":"2002","unstructured":"Levy DE, Darnell JE Jr: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002,3(9):651-662.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"5728_CR18","doi-asserted-by":"publisher","first-page":"C354","DOI":"10.1152\/ajpcell.00513.2009","volume":"299","author":"HA Bluyssen","year":"2010","unstructured":"Bluyssen HA, Rastmanesh MM, Tilburgs C, Jie K, Wesseling S, Goumans MJ, Boer P, Joles JA, Braam B: IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells. Am J Physiol Cell Physiol 2010,299(2):C354-362. 10.1152\/ajpcell.00513.2009","journal-title":"Am J Physiol Cell Physiol"},{"issue":"40","key":"5728_CR19","doi-asserted-by":"publisher","first-page":"41679","DOI":"10.1074\/jbc.M406413200","volume":"279","author":"Y Qing","year":"2004","unstructured":"Qing Y, Stark GR: Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem 2004,279(40):41679-41685. 10.1074\/jbc.M406413200","journal-title":"J Biol Chem"},{"issue":"12","key":"5728_CR20","doi-asserted-by":"publisher","first-page":"8043","DOI":"10.1073\/pnas.122236099","volume":"99","author":"AP Costa-Pereira","year":"2002","unstructured":"Costa-Pereira AP, Tininini S, Strobl B, Alonzi T, Schlaak JF, Is\u2019harc H, Gesualdo I, Newman SJ, Kerr IM, Poli V: Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc Natl Acad Sci USA 2002,99(12):8043-8047. 10.1073\/pnas.122236099","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"5728_CR21","first-page":"106","volume":"19","author":"JY Zhang","year":"2003","unstructured":"Zhang JY, Li Y, Ren YF, Shen BF: Comparison of IL-6-induced STAT1 activation in different responsive cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2003,19(2):106-108.","journal-title":"Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi"},{"issue":"11","key":"5728_CR22","doi-asserted-by":"publisher","first-page":"2102","DOI":"10.1038\/leu.2009.139","volume":"23","author":"G Regis","year":"2009","unstructured":"Regis G, Icardi L, Conti L, Chiarle R, Piva R, Giovarelli M, Poli V, Novelli F: IL-6, but not IFN-gamma, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing. Leukemia 2009,23(11):2102-2108. 10.1038\/leu.2009.139","journal-title":"Leukemia"},{"issue":"20","key":"5728_CR23","doi-asserted-by":"publisher","first-page":"14111","DOI":"10.1074\/jbc.M511797200","volume":"281","author":"HH Ho","year":"2006","unstructured":"Ho HH, Ivashkiv LB: Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem 2006,281(20):14111-14118. 10.1074\/jbc.M511797200","journal-title":"J Biol Chem"},{"issue":"2","key":"5728_CR24","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1046\/j.1471-4159.2003.02012.x","volume":"87","author":"N Kaur","year":"2003","unstructured":"Kaur N, Kim IJ, Higgins D, Halvorsen SW: Induction of an interferon-gamma Stat3 response in nerve cells by pre-treatment with gp130 cytokines. J Neurochem 2003,87(2):437-447. 10.1046\/j.1471-4159.2003.02012.x","journal-title":"J Neurochem"},{"issue":"19","key":"5728_CR25","doi-asserted-by":"publisher","first-page":"4015","DOI":"10.1016\/j.yexcr.2007.08.007","volume":"313","author":"L Thyrell","year":"2007","unstructured":"Thyrell L, Arulampalam V, Hjortsberg L, Farnebo M, Grander D, Pokrovskaja Tamm K: Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity. Exp Cell Res 2007,313(19):4015-4024. 10.1016\/j.yexcr.2007.08.007","journal-title":"Exp Cell Res"},{"issue":"10","key":"5728_CR26","doi-asserted-by":"publisher","first-page":"5034","DOI":"10.4049\/jimmunol.171.10.5034","volume":"171","author":"C Herrero","year":"2003","unstructured":"Herrero C, Hu X, Li WP, Samuels S, Sharif MN, Kotenko S, Ivashkiv LB: Reprogramming of IL-10 activity and signaling by IFN-gamma. J Immunol 2003,171(10):5034-5041.","journal-title":"J Immunol"},{"issue":"3","key":"5728_CR27","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/jmcb\/mjs022","volume":"4","author":"L Chen","year":"2012","unstructured":"Chen L, Wu J: Systems biology for complex diseases. J Mol Cell Biol 2012,4(3):125-126. 10.1093\/jmcb\/mjs022","journal-title":"J Mol Cell Biol"},{"issue":"1-3","key":"5728_CR28","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/S0014-5793(02)03842-5","volume":"534","author":"S Yamada","year":"2003","unstructured":"Yamada S, Shiono S, Joo A, Yoshimura A: Control mechanism of JAK\/STAT signal transduction pathway. FEBS Lett 2003,534(1-3):190-196.","journal-title":"FEBS Lett"},{"issue":"5","key":"5728_CR29","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.febslet.2005.01.009","volume":"579","author":"Z Zi","year":"2005","unstructured":"Zi Z, Cho KH, Sung MH, Xia X, Zheng J, Sun Z: In silico identification of the key components and steps in IFN-gamma induced JAK-STAT signaling pathway. FEBS Lett 2005,579(5):1101-1108. 10.1016\/j.febslet.2005.01.009","journal-title":"FEBS Lett"},{"issue":"5","key":"5728_CR30","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1002\/bit.21026","volume":"95","author":"A Singh","year":"2006","unstructured":"Singh A, Jayaraman A, Hahn J: Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes. Biotechnol Bioeng 2006,95(5):850-862. 10.1002\/bit.21026","journal-title":"Biotechnol Bioeng"},{"issue":"1","key":"5728_CR31","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1049\/iet-syb.2009.0060","volume":"5","author":"C Moya","year":"2011","unstructured":"Moya C, Huang Z, Cheng P, Jayaraman A, Hahn J: Investigation of IL-6 and IL-10 signalling via mathematical modelling. IET Syst Biol 2011,5(1):15. 10.1049\/iet-syb.2009.0060","journal-title":"IET Syst Biol"},{"issue":"5","key":"5728_CR32","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/S0092-8674(00)81443-9","volume":"93","author":"X Chen","year":"1998","unstructured":"Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J: Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 1998,93(5):827-839. 10.1016\/S0092-8674(00)81443-9","journal-title":"Cell"},{"issue":"6689","key":"5728_CR33","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/28101","volume":"394","author":"S Becker","year":"1998","unstructured":"Becker S, Groner B, Muller CW: Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature 1998,394(6689):145-151. 10.1038\/28101","journal-title":"Nature"},{"issue":"7","key":"5728_CR34","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1002\/j.1460-2075.1994.tb06422.x","volume":"13","author":"AC Greenlund","year":"1994","unstructured":"Greenlund AC, Farrar MA, Viviano BL, Schreiber RD: Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J 1994,13(7):1591-1600.","journal-title":"EMBO J"},{"issue":"5202","key":"5728_CR35","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1126\/science.7871432","volume":"267","author":"MH Heim","year":"1995","unstructured":"Heim MH, Kerr IM, Stark GR, Darnell JE Jr: Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 1995,267(5202):1347-1349. 10.1126\/science.7871432","journal-title":"Science"},{"issue":"22","key":"5728_CR36","doi-asserted-by":"publisher","first-page":"12999","DOI":"10.1074\/jbc.271.22.12999","volume":"271","author":"U Hemmann","year":"1996","unstructured":"Hemmann U, Gerhartz C, Heesel B, Sasse J, Kurapkat G, Grotzinger J, Wollmer A, Zhong Z, Darnell JE Jr, Graeve L: Differential activation of acute phase response factor\/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. II. Src homology SH2 domains define the specificity of stat factor activation. J Biol Chem 1996,271(22):12999-13007. 10.1074\/jbc.271.22.12999","journal-title":"J Biol Chem"},{"issue":"6455","key":"5728_CR37","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/366580a0","volume":"366","author":"K Shuai","year":"1993","unstructured":"Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE: Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 1993,366(6455):580-583. 10.1038\/366580a0","journal-title":"Nature"},{"issue":"11","key":"5728_CR38","doi-asserted-by":"publisher","first-page":"5961","DOI":"10.1074\/jbc.271.11.5961","volume":"271","author":"A Kaptein","year":"1996","unstructured":"Kaptein A, Paillard V, Saunders M: Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. J Biol Chem 1996,271(11):5961-5964. 10.1074\/jbc.271.11.5961","journal-title":"J Biol Chem"},{"issue":"18","key":"5728_CR39","doi-asserted-by":"publisher","first-page":"16117","DOI":"10.1074\/jbc.M300261200","volume":"278","author":"M Wiederkehr-Adam","year":"2003","unstructured":"Wiederkehr-Adam M, Ernst P, Muller K, Bieck E, Gombert FO, Ottl J, Graff P, Grossmuller F, Heim MH: Characterization of phosphopeptide motifs specific for the Src homology 2 domains of signal transducer and activator of transcription 1 (STAT1) and STAT3. J Biol Chem 2003,278(18):16117-16128. 10.1074\/jbc.M300261200","journal-title":"J Biol Chem"},{"key":"5728_CR40","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1042\/bse0450109","volume":"45","author":"AC Pfeifer","year":"2008","unstructured":"Pfeifer AC, Timmer J, Klingmuller U: Systems biology of JAK\/STAT signalling. Essays Biochem 2008, 45: 109-120. 10.1042\/BSE0450109","journal-title":"Essays Biochem"},{"issue":"6","key":"5728_CR41","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1046\/j.1365-2443.1999.00263.x","volume":"4","author":"A Sasaki","year":"1999","unstructured":"Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A: 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(6):339-351. 10.1046\/j.1365-2443.1999.00263.x","journal-title":"Genes Cells"},{"issue":"1","key":"5728_CR42","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1074\/jbc.M210552200","volume":"278","author":"U Lehmann","year":"2003","unstructured":"Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J: SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem 2003,278(1):661-671.","journal-title":"J Biol Chem"},{"issue":"29","key":"5728_CR43","doi-asserted-by":"publisher","first-page":"9229","DOI":"10.1021\/bi0259507","volume":"41","author":"D De Souza","year":"2002","unstructured":"De Souza D, Fabri LJ, Nash A, Hilton DJ, Nicola NA, Baca M: SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 2002,41(29):9229-9236. 10.1021\/bi0259507","journal-title":"Biochemistry"},{"issue":"3","key":"5728_CR44","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S1074-7613(00)00028-5","volume":"13","author":"XP Chen","year":"2000","unstructured":"Chen XP, Losman JA, Rothman P: SOCS proteins, regulators of intracellular signaling. Immunity 2000,13(3):287-290. 10.1016\/S1074-7613(00)00028-5","journal-title":"Immunity"},{"issue":"5","key":"5728_CR45","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S0092-8674(00)80047-1","volume":"98","author":"WS Alexander","year":"1999","unstructured":"Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM: SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999,98(5):597-608. 10.1016\/S0092-8674(00)80047-1","journal-title":"Cell"},{"issue":"6","key":"5728_CR46","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/ni931","volume":"4","author":"BA Croker","year":"2003","unstructured":"Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, Robb L, Greenhalgh CJ, Forster I, Clausen BE: SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 2003,4(6):540-545. 10.1038\/ni931","journal-title":"Nat Immunol"},{"issue":"2","key":"5728_CR47","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/S0006-291X(02)03071-1","volume":"301","author":"B He","year":"2003","unstructured":"He B, You L, Uematsu K, Matsangou M, Xu Z, He M, McCormick F, Jablons DM: Cloning and characterization of a functional promoter of the human SOCS-3 gene. Biochem Biophys Res Commun 2003,301(2):386-391. 10.1016\/S0006-291X(02)03071-1","journal-title":"Biochem Biophys Res Commun"},{"issue":"12","key":"5728_CR48","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.cellsig.2005.03.010","volume":"17","author":"S Haan","year":"2005","unstructured":"Haan S, Keller JF, Behrmann I, Heinrich PC, Haan C: Multiple reasons for an inefficient STAT1 response upon IL-6-type cytokine stimulation. Cell Signal 2005,17(12):1542-1550. 10.1016\/j.cellsig.2005.03.010","journal-title":"Cell Signal"},{"issue":"4","key":"5728_CR49","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1128\/MCB.19.4.2913","volume":"19","author":"LH Milocco","year":"1999","unstructured":"Milocco LH, Haslam JA, Rosen J, Seidel HM: Design of conditionally active STATs: insights into STAT activation and gene regulatory function. Mol Cell Biol 1999,19(4):2913-2920.","journal-title":"Mol Cell Biol"},{"issue":"3","key":"5728_CR50","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1093\/emboj\/21.3.344","volume":"21","author":"T Meyer","year":"2002","unstructured":"Meyer T, Begitt A, Lodige I, van Rossum M, Vinkemeier U: Constitutive and IFN-gamma-induced nuclear import of STAT1 proceed through independent pathways. EMBO J 2002,21(3):344-354. 10.1093\/emboj\/21.3.344","journal-title":"EMBO J"},{"issue":"18","key":"5728_CR51","doi-asserted-by":"publisher","first-page":"10188","DOI":"10.1073\/pnas.96.18.10188","volume":"96","author":"RL Haspel","year":"1999","unstructured":"Haspel RL, Darnell JE Jr: A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. Proc Natl Acad Sci USA 1999,96(18):10188-10193. 10.1073\/pnas.96.18.10188","journal-title":"Proc Natl Acad Sci USA"},{"issue":"22","key":"5728_CR52","doi-asserted-by":"publisher","first-page":"6196","DOI":"10.1093\/emboj\/19.22.6196","volume":"19","author":"KM McBride","year":"2000","unstructured":"McBride KM, McDonald C, Reich NC: Nuclear export signal located within theDNA-binding domain of the STAT1transcription factor. EMBO J 2000,19(22):6196-6206. 10.1093\/emboj\/19.22.6196","journal-title":"EMBO J"},{"issue":"3","key":"5728_CR53","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S1359-6101(97)00009-9","volume":"8","author":"S Pestka","year":"1997","unstructured":"Pestka S, Kotenko SV, Muthukumaran G, Izotova LS, Cook JR, Garotta G: The interferon gamma (IFN-gamma) receptor: a paradigm for the multichain cytokine receptor. Cytokine Growth Factor Rev 1997,8(3):189-206. 10.1016\/S1359-6101(97)00009-9","journal-title":"Cytokine Growth Factor Rev"},{"issue":"5202","key":"5728_CR54","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1126\/science.7871433","volume":"267","author":"N Stahl","year":"1995","unstructured":"Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD: Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 1995,267(5202):1349-1353. 10.1126\/science.7871433","journal-title":"Science"},{"issue":"7","key":"5728_CR55","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/j.1460-2075.1995.tb07128.x","volume":"14","author":"D Guschin","year":"1995","unstructured":"Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F, Pellegrini S, Yasukawa K, Heinrich P, Stark GR: A major role for the protein tyrosine kinase JAK1 in the JAK\/STAT signal transduction pathway in response to interleukin-6. EMBO J 1995,14(7):1421-1429.","journal-title":"EMBO J"},{"issue":"42","key":"5728_CR56","doi-asserted-by":"crossref","first-page":"6406","DOI":"10.1038\/sj.onc.1208788","volume":"24","author":"Y Niwa","year":"2005","unstructured":"Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H: Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK\/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 2005,24(42):6406-6417.","journal-title":"Oncogene"},{"key":"5728_CR57","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1186\/1471-2407-12-318","volume":"12","author":"LY Dimberg","year":"2012","unstructured":"Dimberg LY, Dimberg A, Ivarsson K, Fryknas M, Rickardson L, Tobin G, Ekman S, Larsson R, Gullberg U, Nilsson K: Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer 2012, 12: 318. 10.1186\/1471-2407-12-318","journal-title":"BMC Cancer"},{"issue":"3","key":"5728_CR58","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/jlb.65.3.391","volume":"65","author":"E Caldenhoven","year":"1999","unstructured":"Caldenhoven E, Buitenhuis M, van Dijk TB, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP: Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils. J Leukoc Biol 1999,65(3):391-396.","journal-title":"J Leukoc Biol"},{"issue":"8","key":"5728_CR59","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1002\/cmdc.201100194","volume":"6","author":"S Fletcher","year":"2011","unstructured":"Fletcher S, Page BD, Zhang X, Yue P, Li ZH, Sharmeen S, Singh J, Zhao W, Schimmer AD, Trudel S: Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules. ChemMedChem 2011,6(8):1459-1470. 10.1002\/cmdc.201100194","journal-title":"ChemMedChem"},{"key":"5728_CR60","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1476-4598-11-12","volume":"11","author":"I Souissi","year":"2012","unstructured":"Souissi I, Ladam P, Cognet JA, Le Coquil S, Varin-Blank N, Baran-Marszak F, Metelev V, Fagard R: A STAT3-inhibitory hairpin decoy oligodeoxynucleotide discriminates between STAT1 and STAT3 and induces death in a human colon carcinoma cell line. Mol Cancer 2012, 11: 12. 10.1186\/1476-4598-11-12","journal-title":"Mol Cancer"},{"issue":"24","key":"5728_CR61","doi-asserted-by":"publisher","first-page":"3067","DOI":"10.1093\/bioinformatics\/btl485","volume":"22","author":"S Hoops","year":"2006","unstructured":"Hoops S, Sahle S, Gauges R, Lee C, Pahle J, Simus N, Singhal M, Xu L, Mendes P, Kummer U: COPASI-a COmplex PAthway SImulator. Bioinformatics 2006,22(24):3067-3074. 10.1093\/bioinformatics\/btl485","journal-title":"Bioinformatics"},{"issue":"2 Suppl","key":"5728_CR62","first-page":"S81","volume":"7","author":"A Funahashi","year":"2007","unstructured":"Funahashi A, Jouraku A, Matsuoka Y, Kitano H: Integration of cell designer and SABIO-RK. In Silico Biol 2007,7(2 Suppl):S81-90.","journal-title":"In Silico Biol"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-14-41.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T22:26:13Z","timestamp":1630535173000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-14-41"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,6]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["5728"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-14-41","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,6]]},"assertion":[{"value":"19 September 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"41"}}