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A Road Map for Those Who Don't Know JAK-STAT

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Science  31 May 2002:
Vol. 296, Issue 5573, pp. 1653-1655
DOI: 10.1126/science.1071545

Abstract

The Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway transmits information received from extracellular polypeptide signals, through transmembrane receptors, directly to target gene promoters in the nucleus, providing a mechanism for transcriptional regulation without second messengers. Evolutionarily conserved in eukaryotic organisms from slime molds to humans, JAK-STAT signaling appears to be an early adaptation to facilitate intercellular communication that has co-evolved with myriad cellular signaling events. This co-evolution has given rise to highly adapted, ligand-specific signaling pathways that control gene expression. In addition, the JAK-STAT signaling pathways are regulated by a vast array of intrinsic and environmental stimuli, which can add plasticity to the response of a cell or tissue.

Extracellular signaling polypeptides, such as growth factors or cytokines, are recognized by specific transmembrane receptors or receptor complexes on target cells. One consequence of this recognition is a rapid reprogramming or alteration in the pattern of expressed genes in the target cell. In many cases, the immediate responding genes (those that undergo increased transcription in the absence of new protein synthesis) are controlled by a family of transcription-regulating signaling proteins named signal transducer and activator of transcription (STAT). Intercellular signaling is critical for developmental regulation, growth control, and homeostasis in multicellular organisms, and STAT pathways have been found in slime molds, worms, flies, and vertebrates but are absent from fungi and plants (1). In mammals, there are seven STAT genes,STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, and STAT6. There is sufficient diversity in the STAT amino acid sequences and their tissue-specific distributions to account for their diverse roles in responses to extracellular signaling proteins. STAT proteins are inactive as transcription factors in the absence of specific receptor stimulation and are localized in the cytoplasm of unstimulated target cells. They are activated rapidly in response to receptor-ligand coupling and are recruited to the intracellular domain of the receptor through specific binding between STAT Src-homology 2 (SH2) domains and receptor phosphotyrosine residues. These SH2-phosphotyrosine interactions are highly specific and are a critical step in determining the specificity of receptor-mediated STAT activation.

Many growth factor receptors have intrinsic tyrosine kinase activity, but most STAT-activating cytokine receptors do not. Instead, the required tyrosine kinase activity is provided by receptor-associated cytoplasmic proteins from the Janus kinase (JAK) family (2). JAKs are also evolutionarily conserved, and there are four JAK proteins in mammalian cells, JAK1, JAK2, JAK3, and TYK2. The fundamental role of JAKs in cytokine signaling is evidenced by the inherited immunodeficiencies caused by mutations that block receptor-JAK interactions or the kinase activity of the JAKs. JAKs bind specifically to intracellular domains of cytokine receptor signaling chains and catalyze ligand-induced phosphorylation of themselves and of intracellular tyrosine residues on the receptor, creating STAT docking sites. Phosphorylation of STATs on activating tyrosine residues leads to STAT homo- and heterodimerization. STAT dimers are rapidly transported from the cytoplasm to the nucleus and are competent for DNA binding. Most STAT dimers recognize an 8– to 10–base pair inverted repeat DNA element with a consensus sequence of 5′-TT(N4–6)AA-3′. Differential binding affinity of a particular activated STAT dimer for a single target DNA sequence is determined by variations in the exact nucleotide sequence (3). This consensus DNA element is usually referred to as a GAS element, reflecting its initial characterization as a γ-interferon activation sequence recognized by STAT1 homodimers (4). The affinity of a STAT-DNA complex for a natural target gene promoter is also determined by cooperative dimer-dimer interactions mediated by NH2-terminal amino acids (5, 6).

Once the activated STAT dimer recognizes a target promoter, the transcription rate from this promoter is dramatically increased. The ability to induce transcription of target genes is an intrinsic property of the STAT dimers, reflecting the ability of STAT transcriptional activation domains to recruit nuclear co-activators that mediate chromatin modifications and communication with the core promoters. STAT-binding elements appear in the context of additional promoter-bound proteins that vary from one gene to another and are required for optimal gene-specific regulation. Examples of complex enhancers in which STATs are critical activating components include the γ-interferon-responsive cell cycle regulator p21WAF1(7, 8) and the interleukin 6 (IL6)-responsive acute phase response protein α-2 macroglobulin (9–11). These examples are certain to represent a large number of STAT-dependent cooperative transcriptional mechanisms. Although the STATs are generally associated with transcriptional activation, examples of STAT-dependent transcriptional repression have also been reported (12–14)

The JAK-STAT signaling pathways do not usually function autonomously; rather, they are regulated by a vast array of intrinsic and environmental stimuli. These complex means of regulation can add plasticity to the transcriptional output in a specific cell or tissue. Diverse protein kinases, including several mitogen-activated protein kinases (MAPKs), phosphorylate STATs on serine residues, allowing additional cellular signaling pathways to potentiate the primary STAT-activating stimulus (15). Similarly, it is possible that additional sites of regulated serine phosphorylation or other posttranslational modifications may regulate attenuation of STAT activity (16, 17).

Negative regulation of the JAK-STAT pathway is accomplished by such common mechanisms as receptor internalization to endocytic vesicles and subsequent receptor degradation. More specific inhibition signals come from protein tyrosine phosphatases that can act at the level of the membrane-associated receptor-kinase complex (18–20) or, in the nucleus, by dephosphorylation of activated STAT dimers and recycling of the latent STAT monomer to the cytoplasm (21,22). The JAKs have their own inhibitors, called suppressor of cytokine signaling (SOCS) proteins, which directly bind to and inactivate the kinases (23). Expression of SOCS genes can be stimulated by the same cytokines that enhance STAT activation, so the SOCS proteins can act in classic feedback inhibition loops. Protein inhibitors of activated STATs (PIAS) bind to phosphorylated STAT dimers, preventing DNA recognition (24). The steady-state and signal-inducible concentrations of all the positive and negative regulators determine the intensity and duration of the signal response in a particular cell type.

The Connections Maps we have constructed for the Signal Transduction Knowledge Environment (STKE) include a generic, or canonical, JAK-STAT pathway (25) and three specific examples of JAK-STAT pathways (Fig. 1), the type I interferon (IFNα/β) pathway that uses STAT1 and STAT2 (26), the type II interferon (IFNγ) pathway that uses STAT1 (27), and the STAT3 pathway that is widely activated in a variety of cellular contexts (28).

Figure 1

. Three examples of signaling in the JAK-STAT pathway. Specific ligand-receptor interactions generate active transcription complexes composed of distinct STAT proteins. Left: Type II IFN (IFNγ) binding induces receptor tyrosine phosphorylation (P) by JAK1 and JAK2 proteins, producing a recruitment site for STAT1. STAT1 dimers form the IFNγ-activated factor (GAF), which translocates to the nucleus and activates transcription from IFNγ target gene promoters containing GAS elements. Center: Type I IFNs (IFNα or IFNβ) stimulate the activity of JAK1 and TYK2 proteins, leading to STAT2 tyrosine phosphorylation. The STAT2 phosphotyrosine is a docking site for latent STAT1. The activated factor ISGF3 is a heterotrimer of STAT1 and STAT2 in association with IRF9, which alone can enter the nucleus, but is retained in the cytoplasm by interactions with STAT2. Right: IL6 activates JAK1 and JAK2, producing a phosphotyrosine docking site for STAT3. STAT3 dimers translocate to the nucleus and activate transcription from target gene promoters containing a GAS-like element, sometimes referred to as the sis-inducible element (SIE). IL6 also activates STAT1, leading to homo- and heterodimers of STAT1 and STAT3 (not illustrated).

The type I interferon (IFNα/β) pathway is mechanistically distinct from the majority of STAT pathways. In this pathway, the endpoint transcription factor is not a simple STAT dimer, but a heterotrimer consisting of a STAT1-STAT2 dimer and an obligatory DNA binding subunit from a member of the interferon regulatory factor family, IRF9. The association of the STATs with IRF9 results in recognition of a distinct DNA response element, the IFN-stimulated response element (ISRE), with the sequence 5′-AGTTTN3TTTCC-3′. The trimeric factor ISGF3 (interferon-stimulated gene factor 3) is the primary signaling mechanism leading to expression of target genes required for innate antiviral immunity in higher organisms. The importance of STAT1 and STAT2 in establishing an initial line of defense is underscored by the finding that these proteins are targeted by virus immune evasion strategies (29, 30).

The type II IFN (IFNγ) pathway is a paradigm for most aspects of JAK-STAT signaling that result in dimeric STAT transcription factors. IFNγ induces the activation of STAT1 homodimers that recognize the GAS element in the promoter of target genes involved in innate and adaptive immunity and is important for shaping antitumor immune responses (31, 32). Germline mutations in STAT1 lead to defective antimicrobial immunity (33).

The third specific pathway focuses on STAT3, which is broadly studied because of its many functions in animal cell growth regulation, inflammation, and early embryonic development resulting from diverse stimuli [reviewed in (34, 35)]. STAT3 is activated by many cytokines that use signaling receptor subunits similar to gp130. Activation of STAT3 occurs in many solid and hematologic tumors and is correlated with growth stimulation and anti-apoptotic effects in malignancies. Many routes lead to STAT3 activation other than cytokine stimuli, including growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), that use tyrosine kinase receptors. Several oncogenic non-receptor tyrosine kinases can activate STAT3, which is required for their ability to malignantly transform cells in culture. In addition, STAT3 is activated in response to oncogenic heterotrimeric guanine nucleotide-binding protein (G protein) subunits through the activation of a cellular non-receptor tyrosine kinase, c-Src, a striking example of cross talk and interconnections between functionally and conceptually distinct signaling pathways through a cellular proto-oncogene (36).

It is anticipated that further connections between the JAK-STAT pathways and the other signal transduction systems illustrated by the STKE Connections Maps will be unveiled, providing diversions along the roads that lead to gene regulation.

  • * To whom correspondence should be addressed. E-mail: curt.horvath{at}mssm.edu

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