JAK-STAT Signaling: From Interferons to Cytokines

Abstract

50 years ago Isaacs and Lindenmann (1Isaacs A. Lindenmann J. Proc. R. Soc. Lond. B. Biol. Sci. 1957; 147: 258-267Crossref PubMed Google Scholar) first described interferons (IFNs) 2The abbreviations used are: IFN, interferon; JAK, Janus kinase; STAT, signal transducers and activators of transcription; JH, JAK homology; γC, γ-chain; SH2, Src homology 2; IL, interleukin; IFNAR, IFN-α receptor chain; ISGF, IFN-stimulated gene factor; ISRE, IFN-stimulated response element; TAD, transcriptional activation domain; GAS, γ-IFN-activated site; aa, amino acid(s); GM-CSF, granulocyte/macrophage-colony-stimulating factor; SOCS, suppressors of cytokine signaling; CBP, CREB-binding factor; pol II, polymerase II; HDAC, histone deacetylase; LIF, leukemia inhibitory factor. as founding members of the cytokine family. Over the next 25 years, these and several other four-helix bundle cytokines were characterized. The subsequent 25 years witnessed an exponential growth in number of four-helix bundle cytokines and their corresponding receptors. The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines induce gene expression, culminating in the identification of the JAK-STAT signaling paradigm (see Fig. 1). Subsequent studies identified 7 STATs and 4 JAKs, providing important insight into how the ∼50 members of the four-helix bundle cytokine family transduce their potent biological responses. This review will briefly summarize this signaling paradigm (reviewed in Refs. 2Kisseleva T. Bhattacharya S. Braunstein J. Schindler C.W. Gene. 2002; 285: 1-24Crossref PubMed Scopus (907) Google Scholar, 3Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2501) Google Scholar, 4Decker T. Muller M. Stockinger S. Nat. Rev. Immunol. 2005; 5: 675-687Crossref PubMed Scopus (381) Google Scholar, 5O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar) and then focus on STAT-dependent transcription. Members of the JAK family, Jak1, Jak2, Jak3, and Tyk2, were initially identified as orphan tyrosine kinases (2Kisseleva T. Bhattacharya S. Braunstein J. Schindler C.W. Gene. 2002; 285: 1-24Crossref PubMed Scopus (907) Google Scholar, 3Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2501) Google Scholar, 5O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar, 6Firmbach-Kraft I. Byers M. Shows T. Dalla-Favera R. Krolewski J.J. Oncogene. 1990; 5: 1329-1336PubMed Google Scholar, 7Wilks A.F. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1603-1607Crossref PubMed Scopus (365) Google Scholar). All exhibited broad patterns of expression, except Jak3, in which expression was restricted to leukocytes. Genetic studies linking Tyk2 to the biological response to type I IFNs (IFN-I; also IFN-α/β) inspired studies associating these kinases with cytokine signaling (2Kisseleva T. Bhattacharya S. Braunstein J. Schindler C.W. Gene. 2002; 285: 1-24Crossref PubMed Scopus (907) Google Scholar, 5O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar, 8Velazquez L. Fellous M. Stark G.R. Pellegrini S. Cell. 1992; 70: 313-322Abstract Full Text PDF PubMed Scopus (709) Google Scholar). Specifically, these studies determined that ligand binding stimulated the rapid activation of receptor-associated JAKs, initiating JAK-STAT signaling (see Fig. 1). JAKs range in size from 120 to 140 kDa and feature seven conserved JAK homology (JH) domains. The two carboxyl-terminal JH regions represent the kinase (JH1/Ki) and pseudo kinase (JH2/ΨKi) domains (see Fig. 2). As with other tyrosine kinases, activation is driven by phosphorylation of critical tyrosines in the “inactivation loop.” The four amino-terminal JH domains (JH7–5 and half of JH4) constitute a FERM (four point one, ezrin, radixin, moesin) domain that mediates association with receptors. Specifically, JAKs associate with the proline-rich, membrane-proximal box1/box2 domain on cytokine receptors. An SH2-related domain (SH2; JH3 and half of JH4), of unknown function, lies between the pseudokinase and FERM domains. Tyk2—Tyk2 associates with receptors for IFN-I, IL-6, IL-10 and IL-12/23 cytokine families (2Kisseleva T. Bhattacharya S. Braunstein J. Schindler C.W. Gene. 2002; 285: 1-24Crossref PubMed Scopus (907) Google Scholar, 9Watford W.T. O'Shea J.J. Immunity. 2006; 25: 695-697Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). In Tyk2-deficient humans, the combined defects in the response to IFN-I, IL-6, IL-10, IL-12, and IL-23 are associated with enhanced allergic and impaired antimicrobial responses (9Watford W.T. O'Shea J.J. Immunity. 2006; 25: 695-697Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). By comparison, Tyk2 knock-out mice exhibit a less