Work

JAK-STAT Signaling: From Interferons to Cytokines

Year: 2007

Type: review

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 severe defect, indicating that murine Tyk2 is more of a response amplifier and not absolutely required (9Watford W.T. O'Shea J.J. Immunity. 2006; 25: 695-697Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Like humans, however, Tyk2-deficient mice exhibit a proclivity toward type 2 immune response (9Watford W.T. O'Shea J.J. Immunity. 2006; 25: 695-697Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). In addition, Tyk2 contributes to the lethal effects of endotoxin through an ill defined and largely Stat1-independent pathway (10Karaghiosoff M. Steinborn R. Kovarik P. Kriegshauser G. Baccarini M. Donabauer B. Reichart U. Kolbe T. Bogdan C. Leanderson T. Levy D. Decker T. Muller M. Nat. Immunol. 2003; 4: 471-477Crossref PubMed Scopus (307) Google Scholar). Jak1—Initially identified in a screen for novel kinases (7Wilks A.F. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1603-1607Crossref PubMed Scopus (365) Google Scholar), biochemical and genetic studies have revealed a functional and physical association with the type I (IFN-α/β), type II (IFN-γ), IL-2, and IL-6 receptors (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). Evidence that the two IFN-α receptor chains, IFNAR1 and IFNAR2, associated with Tyk2 and Jak1, respectively, led to the notion that JAKs activate each other through transphosphorylation. Importantly, Jak1 knockout mice die perinatally, reflecting a defect in LIF (an IL-6 family member) receptor 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). Characterization of Jak1 knock-out tissues, however, confirmed a critical role for this kinase in the response to IFN, IL-10, IL-2/IL-4 and IL-6 cytokine families. Jak2—Initial biochemical studies implicated Jak2 in the response to receptors from the single-chain (i.e. Epo-R, GH-R, Prl-R) and IL-3 (IL-3R, IL-5R, and GM-CSFR) cytokine families, as well as the IFN-γ receptor (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). Consistent with a critical role in definitive erythropoiesis, Jak2 knock-out mice died of anemia at E12.5 (5O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar). Analysis of Jak2–/– tissues confirmed an important role in directing the responses to members of the single-chain, IL-3, and IFN-γ receptor families. Intriguingly, humans with Jak2 mutations exhibit myeloproliferative disorders (11Delhommeau F. Pisani D.F. James C. Casadevall N. Constantinescu S. Vainchenker W. Cell Mol. Life Sci. 2006; 63: 2939-2953Crossref PubMed Scopus (61) Google Scholar). Finally, elegant biochemical studies with chimeric erythropoietin receptors provide compelling evidence that ligand binding drives two receptor associated Jak2s into close proximity, enabling them to activate each other by transphosphorylation (12Remy I. Wilson I.A. Michnick S.W. Science. 1999; 283: 990-993Crossref PubMed Scopus (538) Google Scholar). Jak3—Leukocyte-specific Jak3 exclusively associates with the IL-2 receptor γ-chain (γC). This chain also serves as a component for the receptors of several lymphotrophic cytokines, including IL-4, IL-7, IL-9, IL-15, and IL-21. Underscoring the critical roles that γC and Jak3 play in lymphoid activity, mutations in either molecule are associated with severe combined immunodeficiency disease (5O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar). Intriguingly, Jak3 knock-out mice develop a similar, but less severe, immunodeficiency syndrome (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). Because of the unique role Jak3 plays in regulating lymphocytes, it has become an important pharmaceutical target. The seven members of the mammalian STAT family (STATs 1, 2, 3, 4, 5a, 5b, and 6) range in size from 750 to 900 amino acids and feature several conserved domains, notably including an SH2 domain (see Fig. 2). In resting cells, STATs reside largely in the cytoplasm as inactive homodimers (13Mertens C. Zhong M. Krishnaraj R. Zou W. Chen X. Darnell Jr., J.E. Genes Dev. 2006; 20: 3372-3381Crossref PubMed Scopus (110) Google Scholar). However, upon ligand binding, receptor-associated JAKs become activated (see above), leading to the phosphorylation of specific receptor tyrosine residues (see Fig. 1). These receptor phosphotyrosyl residues direct the SH2-dependent recruitment of specific STATs, which in turn become JAK substrates. Activated STATs are released from the receptor as they reorient into an antiparallel dimer, where the SH2 domain of one STAT binds the phosphotyrosine of the other STAT. Activated STAT dimers translocate to the nucleus and bind to specific enhancer elements. STAT homodimers bind to members of the GAS family of enhancers (a palindrome, TTTCCNGGAAA; Fig. 1). In contrast, IFN-Is promote the formation of Stat1-Stat2 heterodimers, which associate with IRF-9 (IFN regulatory factor) to form ISGF-3 and bind to the ISRE enhancer family (a direct repeat, AGTTTN3TTTCC; Fig. 1). STAT Structure—Biochemical, genetic, and structural studies have identified seven conserved STAT domains, including the amino-terminal (NH2), coiled-coil, DNA-binding (DBD), linker (Lk), SH2, tyrosine activation (Y), and transcriptional activation domains (TAD) (Fig. 2; Ref. 14Becker S. Groner B. Müller C.W. Nature. 1998; 394: 145-151Crossref PubMed Scopus (670) Google Scholar, 15Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell Jr., J.E. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar). The NH2 domain (∼125 residues) is a structurally independent moiety and appears to direct homotypic dimerization of inactive STATs (13Mertens C. Zhong M. Krishnaraj R. Zou W. Chen X. Darnell Jr., J.E. Genes Dev. 2006; 20: 3372-3381Crossref PubMed Scopus (110) Google Scholar). This domain has also been implicated in cooperative DNA binding to tandem GAS elements, as well as in nuclear import and export (16McBride K.M. Reich N.C. Sci. STKE 2003. 2003; : RE13Google Scholar, 17Vinkemeier U. J. Cell Biol. PubMed Scopus Google Scholar). The domain of a bundle that from the This domain a and binds The DNA-binding domain of a that binding to the GAS family of enhancers with The corresponding of the Stat1-Stat2 has not been The linker domain an between the DNA-binding and dimerization domains. important role in receptor recruitment and the SH2 domain is the conserved The tyrosine activation domain is to the SH2 (i.e. The carboxyl-terminal which STAT family constitute the This an opportunity to associate with transcriptional (see founding STAT was initially identified as a component of the (Fig. Ref. C. Darnell J.E. Science. 1992; PubMed Scopus Google Scholar). Subsequent studies determined that the of homodimers Schindler C. Darnell J.E. Science. 1992; PubMed Scopus Google Scholar). studies confirmed the role that plays in the biological response to type I and type II IFNs D. R. M. Schreiber R.D. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J.E. R. Levy D.E. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with humans exhibit to and A. S. G. J. A. A. C. C. J. C. L. Schreiber R.D. C. A. J. 2006; PubMed Scopus Google Scholar). Intriguingly, to promote and This the and associated with (see the of several cytokines to activate and members of the and IL-6 an to a more was also initially identified as a component of and genetic studies have revealed that plays a role in the biological response to type I a critical role for in regulating the T. Muller M. Stockinger S. Nat. Rev. Immunol. 2005; 5: 675-687Crossref PubMed Scopus (381) Google Scholar, C. S. Schindler C. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). the of this family. In to the STAT in in with a TAD, is evidence that homodimers form bind with Finally, the by which is to was initially identified as an that gene expression S. Y. M. S. T. T. M. T. Cell. Full Text PDF PubMed Scopus Google Scholar). is to transduce for the IL-6 LIF, and IL-10 families, as well as and (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). studies in have that is activated by several growth and gene has a role for (i.e. die at (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 In contrast, specific have an important role for (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. 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Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.r700016200

Authors: Christian Schindler, David E. Levy, Thomas Decker

Institutions: Columbia University, New York University, University of Vienna, Max Perutz Labs

Language: English

Topic: Cytokine Signaling Pathways and Interactions

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $3,430

Funder: Austrian Science Fund