ReviewInteferons pen the JAK–STAT pathway
Introduction
Interferons (IFNs), founding members of the cytokine family, were first described by Isaacs and Lindenmann more than 50 years ago [1]. Over the subsequent 25 years, these four-helix bundle cytokines were purified to reveal a surprising biochemical diversity [2]. Concomitant developments in cloning technologies provided both the nascent biotechnology industry with one of its first products and revealed that IFNs can be divided into two major families. Type I IFNs, which included fibroblast (a.k.a.—IFN-β) and leukocyte (a.k.a.—IFN-α's) IFNs, was the larger and more pleiotropic family, whereas type II IFN was represented by a single member, immune IFN (a.k.a.—IFN-γ).
The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines mediate their potent biological responses. Initial cDNA expression studies identified a unique set of IFN stimulated genes (ISGs), as well as distinct type I and II receptors [2], [3], [4]. Characterization of the ability of IFN-α to drive ISG expression led to the identification of Signal transducers and activators of transcription (Stat)-1 and Stat2 [5], [6], [7]. Subsequent studies implicated Tyk2 (a Janus kinase; a.k.a., JAK) and tyrosine phosphorylation in STAT-dependent signaling [8], [9], [10]. Over the next several years 7 STATs and 4 JAKs were identified, providing important insight into how the ∼50 members of the four-helix bundle cytokine family transduce their potent biological responses (see Table 1). Parallel, but more difficult studies on STAT signal decay identified several families of negative regulators, most notably members of the Suppressors of Cytokine Signaling (SOCS) family (see [154], [155] this issue; reviewed in Refs. [11], [12], [13], [14]).
Section snippets
Discovery of the JAK–STAT signaling paradigm
Shortly after the isolation of the first ISGs, an IFN-I specific enhancer, the ISRE (IFN Stimulated Response Element; AGTTTN3TTTCC), was identified [4], [6], [15]. Analysis of IFN-α stimulated nuclear extracts revealed three distinct ISRE binding complexes: IFN-I Stimulated Gene Factor 1 (ISGF-1; a.k.a. IRF-2); ISGF-2 (a.k.a. IRF-1); and ISGF-3, whose activation correlated directly with the expression of immediate early ISGs [6], [15], [16]. Purification of ISGF-3 led to identification of four
The Janus kinases (JAK) family
The four JAK family members, Jak1, Jak2, Jak3 and Tyk2, range in size from 120 kDa to 140 kDa, and except for Jak3 (leukocyte-JAK [36]), are expressed in most tissues (reviewed in Refs. [46], [47]). This kinase family features seven conserved JAK homology (JH) domains (see Fig. 1), notably including a tandem set of carboxy terminal kinase domains, where only JH1 has bona fide catalytic activity (Ki). JH2 is referred to as the pseudo kinase (ΨKi) domain. Reminiscent of other kinases, activation is
The STAT family of transcription factors
The seven mammals STAT (Stats1–6, 5a and 5b) range in size from 750 and 900 amino acids (see Fig. 1). Both their chromosomal distribution and homologues in model eukaryotes, suggest this family arose from a single primordial gene, as the need for cell-to-cell communication increased [60], [61]. Stat3 and Stat5 are most closely related to those homologues found in model eukaryotes, like Dictyostelium, C. elegans and Drosophila (see article number 4; [60]). Notably, the single Drosophila STAT
Regulating STAT activity
A characteristic feature of JAK–STAT signaling is its rapid onset and decay. Consistent with this, STATs associate with several classes of regulators, including those that promote covalent modifications in addition to canonical tyrosine phosphorylation. The best-characterized negative regulators include phosphatases, nuclear import/export machinery and members of the SOCS family. However, other negative regulators like PIAS and Nmi have been reported [133], [134].
A bright future
Characterization of the ability of IFNs to direct an antiviral response led to the identification of the JAK–STAT signaling cascade, and provided insight into how the more than 50 members of the four-helix bundle cytokine family transduce their biological response (see Table 1). Future studies are likely to exploit conditional gene targeting, as well as improving pharmaceutical agents to explore how these pathways regulate immune homeostasis in vivo. This is not only likely to include the
References (158)
- et al.
A protein tyrosine kinase in the interferon alpha/beta signaling pathway
Cell
(1992) - et al.
Cytokine signaling in 2002: new surprises in the Jak/Stat pathway
Cell
(2002) - et al.
Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA
Cell
(1998) - et al.
Human CD34(+) bone marrow cells regulate stromal production of interleukin-6 and granulocyte colony-stimulating factor and increase the colony-stimulating activity of stroma
Blood
(1998) - et al.
Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions
Cell
(1994) - et al.
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase
Cell
(1993) - et al.
Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway
Cell
(1994) - et al.
JAK–STAT signaling: from interferons to cytokines
J Biol Chem
(2007) - et al.
Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses
Cell
(1998) - et al.
Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis
Cell
(1998)
Jak2 is essential for signaling through a variety of cytokine receptors
Cell
Developmental defects of lymphoid cells in Jak3 kinase-deficient mice
Immunity
Partial impairment of cytokine responses in Tyk2-deficient mice
Immunity
Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function
Immunity
Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity
Immunity
Signaling through the JAK/STAT pathway, recent advances and future challenges
Gene
Structure of the mouse stat 3/5 locus: evolution from drosophila to zebrafish to mouse
Genomics
Structure of the unphosphorylated STAT5a dimer
J Biol Chem
Structural bases of unphosphorylated STAT1 association and receptor binding
Mol Cell
STATs dimerize in the absence of phosphorylation
J Biol Chem
An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1
J Biol Chem
Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a
J Biol Chem
SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling
Immunity
Cooperation between STAT3 and c-jun suppresses Fas transcription
Mol Cell
Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease
Cell
Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK–STAT signaling pathway
Cell
Immune response in Stat2 knockout mice
Immunity
Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling
Immunity
Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway
Cell
Virus interference. I. The interferon
Proc Roy Soc Lond B Biol Sci
The human interferon alpha species and receptors
Biopolymers
Interferon-stimulated transcription: isolation of an inducible gene and identification of its regulatory region
Proc Natl Acad Sci USA
Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element
Proc Natl Acad Sci USA
The proteins of ISGF-3, the IFN-α induced transcription activator, define a new family of signal transducers
Proc Natl Acad Sci USA
Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes
Proc Natl Acad Sci USA
Proteins of transcription factor ISGF-3: one gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon alpha
Proc Natl Acad Sci USA
Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor
Science
Activation of transcription by IFN-γ: tyrosine phosphorylation of a 91-kDa DNA binding protein
Science
Stats: transcriptional control and biological impact
Nat Rev Mol Cell Biol
The yin and yang of type I interferon activity in bacterial infection
Nat Rev Immunol
The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response
Annu Rev Immunol
Transcriptional regulation of interferon-stimulated genes: a DNA response element and induced proteins that recognize it
Cold Spring Harb Symp Quant Biol
ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains
Proc Natl Acad Sci USA
Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro
Genes Dev
Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins
Mol Cell Biol
Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein
Science
Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons
Mol Cell Biol
The response of gamma interferon activation factor is under developmental control in cells of the macrophage lineage
Mol Cell Biol
The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds
Mol Cell Biol
Interferon gamma-induced transcription of the high-affinity Fc receptor for IgG requires assembly of a complex that includes the 91-kDa subunit of transcription factor ISGF3
Proc Natl Acad Sci USA
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