title: IFN signaling: how a non-canonical model led to the development of IFN mimetics.
abstract: The classical model of cytokine signaling dominates our view of specific gene activation by cytokines such as the interferons (IFNs). The importance of the model extends beyond cytokines and applies to hormones such as growth hormone (GH) and insulin, and growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). According to this model, ligand activates the cell via interaction with the extracellular domain of the receptor. This results in activation of receptor or receptor-associated tyrosine kinases, primarily of the Janus activated kinase (JAK) family, phosphorylation and dimerization of the signal transducer and activator of transcription (STAT) transcription factors, which dissociate from the receptor cytoplasmic domain and translocate to the nucleus. This view ascribes no further role to the ligand, JAK kinase, or receptor in either specific gene activation or the associated epigenetic events. The presence of dimeric STATs in the nucleus essentially explains it all. Our studies have resulted in the development of a non-canonical, more complex model of IFNγ signaling that is akin to that of steroid hormone (SH)/steroid receptor (SR) signaling. We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events. We found that the type I IFN system functions similarly. The fact that GH receptor, insulin receptor, EGF receptor, and FGF receptor undergo nuclear translocation upon ligand binding suggests that they may also function similarly. The SH/SR nature of type I and II IFN signaling provides insight into the specificity of signaling by members of cytokine families. The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Johnson
authors.forename: Ezra Neptune
authors.initials: EN
authors.lastname: Noon-Song
authors.forename: Rea
authors.initials: R
authors.lastname: Dabelic
authors.forename: Chulbul M
authors.initials: CM
authors.lastname: Ahmed
keywords: JAK/STAT signaling; cytokines; interferon mimetics; interferon receptor; interferon signaling
references.citation: Cytokine. 2001 Aug 21;15(4):175-87
references.pmid: 11563878
references.citation: Physiol Rev. 2003 Jan;83(1):163-82
references.pmid: 12506129
references.citation: Nature. 2009 Oct 8;461(7265):819-22
references.pmid: 19783980
references.citation: Biochem Biophys Res Commun. 1994 May 30;201(1):215-21
references.pmid: 8198577
references.citation: Growth Factors. 2011 Dec;29(6):245-52
references.pmid: 21892841
references.citation: DNA Cell Biol. 2007 Dec;26(12):811-26
references.pmid: 18021009
references.citation: Nat Immunol. 2011 Mar;12(3):247-54
references.pmid: 21278738
references.citation: J Interferon Cytokine Res. 2001 Jun;21(6):399-408
references.pmid: 11440637
references.citation: J Interferon Cytokine Res. 2000 Jun;20(6):565-76
references.pmid: 10888113
references.citation: Prog Brain Res. 2010;181:153-76
references.pmid: 20478437
references.citation: Biochem Biophys Res Commun. 1998 Dec 30;253(3):639-47
references.pmid: 9918780
references.citation: Cell Biosci. 2012 Apr 20;2(1):13
references.pmid: 22520625
references.citation: Cell. 2011 Aug 19;146(4):621-32
references.pmid: 21854986
references.citation: J Immunol. 2002 Aug 15;169(4):1959-69
references.pmid: 12165521
references.citation: PLoS One. 2011 May 05;6(5):e19605
references.pmid: 21573184
references.citation: Mol Endocrinol. 2010 Nov;24(11):2088-98
references.pmid: 20484412
references.citation: Drug Saf. 2003;26(11):815-27
references.pmid: 12908850
references.citation: Cancer Res. 2005 Jan 1;65(1):338-48
references.pmid: 15665312
references.citation: J Interferon Cytokine Res. 1996 Jul;16(7):507-10
references.pmid: 8836915
references.citation: Nucl Recept Signal. 2007 May 17;5:e005
references.pmid: 17525795
references.citation: Clin Microbiol Rev. 2001 Oct;14(4):778-809, table of contents
references.pmid: 11585785
references.citation: Curr Opin Cell Biol. 2003 Apr;15(2):143-8
references.pmid: 12648669
references.citation: J Biol Chem. 1997 Jul 11;272(28):17694-702
references.pmid: 9211920
references.citation: J Cell Sci. 2000 Aug;113 ( Pt 15):2771-81
references.pmid: 10893192
references.citation: J Biol Chem. 2000 Jul 28;275(30):22995-3004
references.pmid: 10811814
references.citation: Nat Cell Biol. 2011 Jan;13(1):13-21
references.pmid: 21151131
references.citation: J Biol Chem. 2002 Apr 5;277(14):12067-74
references.pmid: 11815625
references.citation: Science. 1990 Sep 28;249(4976):1567-70
references.pmid: 1699274
references.citation: N Engl J Med. 2013 Jan 10;368(2):161-70
references.pmid: 23301733
references.citation: Nat Genet. 2006 Sep;38(9):1071-6
references.pmid: 16892059
references.citation: J Virol. 2000 Dec;74(23):11230-9
references.pmid: 11070021
references.citation: J Cell Biochem. 2006 Aug 15;98(6):1570-83
references.pmid: 16552725
references.citation: J Immunol. 2006 Jul 1;177(1):315-21
references.pmid: 16785527
references.citation: Traffic. 2005 Oct;6(10):947-54
references.pmid: 16138907
references.citation: Cancer. 1998 May 1;82(9):1677-81
references.pmid: 9576288
references.citation: Cell. 1998 May 29;93(5):827-39
references.pmid: 9630226
references.citation: Biochem Biophys Res Commun. 2010 Sep 3;399(4):498-504
references.pmid: 20674546
references.citation: J Neurol Sci. 2009 Dec;287 Suppl 1:S30-6
references.pmid: 20106346
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18962-7
references.pmid: 16365288
references.citation: Future Med Chem. 2012 Aug;4(12):1527-31
references.pmid: 22917241
references.citation: J Biol Chem. 2001 Aug 17;276(33):30812-8
references.pmid: 11399767
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3089-98
references.pmid: 12799413
references.citation: Mol Biol Cell. 2007 Mar;18(3):1064-72
references.pmid: 17215517
references.citation: J Immunol. 1995 Dec 15;155(12):5617-22
references.pmid: 7499845
references.citation: J Mol Biol. 2000 May 26;299(1):169-79
references.pmid: 10860730
references.citation: Science. 2002 Feb 1;295(5556):813-8
references.pmid: 11823631
references.citation: Endocrinology. 1996 Sep;137(9):4037-45
references.pmid: 8756581
references.citation: J Biol Chem. 2010 Dec 3;285(49):38720-9
references.pmid: 20937808
references.citation: Sci STKE. 2007 Dec 04;2007(415):pe69
references.pmid: 18056914
references.citation: Mol Biol Cell. 2005 Apr;16(4):1569-83
references.pmid: 15659653
references.citation: Arch Med Res. 2009 Jul;40(5):331-8
references.pmid: 19766894
references.citation: Biochem Biophys Res Commun. 2011 Jul 8;410(3):648-53
references.pmid: 21689637
references.citation: J Immunol. 2010 Jul 15;185(2):1103-13
references.pmid: 20543109
references.citation: Biochem J. 2012 Apr 15;443(2):329-38
references.pmid: 22452815
references.citation: J Interferon Cytokine Res. 2011 Jan;31(1):33-40
references.pmid: 21166594
references.citation: J Immunol. 2007 Apr 1;178(7):4576-83
references.pmid: 17372016
references.citation: J Biol Chem. 2008 Feb 29;283(9):5258-66
references.pmid: 18158285
references.citation: Ther Adv Neurol Disord. 2012 Jul;5(4):205-20
references.pmid: 22783370
references.citation: Steroids. 2009 Jul;74(7):568-72
references.pmid: 19135465
references.citation: J Interferon Cytokine Res. 1996 Oct;16(10):813-7
references.pmid: 8910766
references.citation: FEBS Lett. 2004 Dec 17;578(3):207-10
references.pmid: 15589821
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12270-4
references.pmid: 8618883
references.citation: Epigenetics. 2011 Apr;6(4):516-25
references.pmid: 21266852
references.citation: Immunol Lett. 2005 Jan 15;96(1):11-26
references.pmid: 15585303
references.citation: Int J Biochem Cell Biol. 2008;40(10):1984-9
references.pmid: 17888716
references.citation: Nat Immunol. 2012 Jul 19;13(8):722-8
references.pmid: 22814351
references.citation: Cancer Res. 2011 May 15;71(10):3720-31
references.pmid: 21464042
references.citation: Bioessays. 2004 Sep;26(9):993-1004
references.pmid: 15351969
references.citation: Mol Cell. 2006 Nov 3;24(3):367-81
references.pmid: 17081988
references.citation: Semin Oncol. 1997 Jun;24(3 Suppl 9):S9-18-S9-40
references.pmid: 9208871
references.citation: Cytokine Growth Factor Rev. 2003 Oct;14(5):361-8
references.pmid: 12948519
references.citation: Nat Rev Immunol. 2005 May;5(5):375-86
references.pmid: 15864272
references.citation: Cytokine Growth Factor Rev. 2008 Oct-Dec;19(5-6):383-94
references.pmid: 18929502
references.citation: Arch Neurol. 2005 May;62(5):785-92
references.pmid: 15883267
references.citation: J Neuroimmunol. 2013 Jan 15;254(1-2):101-9
references.pmid: 23110939
references.citation: Nat Cell Biol. 2001 Sep;3(9):802-8
references.pmid: 11533659
references.citation: Nature. 2007 May 24;447(7143):407-12
references.pmid: 17522673
references.citation: J Cell Sci. 2006 Oct 15;119(Pt 20):4332-41
references.pmid: 17003104
references.citation: Mol Cell Biol. 2006 Aug;26(15):5663-74
references.pmid: 16847321
references.citation: Traffic. 2012 May;13(5):650-64
references.pmid: 22321063
references.citation: Expert Rev Neurother. 2005 Mar;5(2):153-64
references.pmid: 15853486
references.citation: Mol Biol Cell. 2006 Jul;17(7):2896-909
references.pmid: 16624862
references.citation: J Virol. 2005 May;79(9):5632-9
references.pmid: 15827178