Signal transducer and activator of transcription (STAT) proteins are latent in the cytoplasm until activated through receptor-mediated tyrosine phosphorylation — often, but not exclusively by kinases of the JAK family — leading to SH2-domain-dependent dimerization and nuclear translocation.
STAT nuclear translocation depends on sequence motifs formed during dimerization, and they remain nuclear until dephosphorylated by a nuclear tyrosine phosphatase, allowing subsequent active nuclear export. So, the most common cycle of STAT activation involves cytoplasmic recruitment to activated cell-surface receptors, tyrosine phosphorylation, receptor release and dimerization, nuclear translocation and DNA binding, coactivator recruitment and gene transcription, nuclear dephosphorylation, and return to the cytoplasm by active nuclear export, followed by possible reactivation due to continued kinase activity.
Negative regulators of STATs include cytoplasmic tyrosine phosphatases that counteract Janus kinase (JAK) action, induced suppressor of cytokine signalling (SOCS) proteins that inhibit receptor and JAK function, proteins that inhibit activated STAT (PIAS) proteins that prevent STAT DNA binding, nuclear phosphatases that deactivate STATs, and truncated STAT proteins that can function in a dominant-inhibitory mode.
Transcriptional activation of target gene expression relies on coactivator recruitment by STAT transactivation domains, relying on a variety of acetyltransferases, minichromosome maintenance (MCM) proteins, and additional factors yet to be identified.
STAT proteins participate in many signalling systems, providing an almost universal paradigm for signalling from cytokine receptors and a commonly used system for growth factor receptors. Target genes dependent on STATs influence growth, survival, apoptosis, host defence, stress and differentiation functions, depending on the signalling pathway and the target tissue. Characterization of JAK and STAT mutations in a variety of organisms, from slime moulds to flies to mice to humans, is beginning to clarify the variety of STAT-dependent biological processes in vivo.
Extracellular proteins bound to cell-surface receptors can change nuclear gene expression patterns in minutes, with far-reaching consequences for development, cell growth and homeostasis. The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways. In addition to several roles in normal cell decisions, dysregulation of STAT function contributes to human disease, making the study of these proteins an important topic of current research.
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Work in the authors' laboratories was supported by grants from the NIH.
- SH2 DOMAIN
(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.
Protein that mediates polypeptide folding or the assembly of another polypeptide-containing structure but does not form part of the completed structure or participate in its biological function.
Cancer of the liver.
- INNATE IMMUNE RESPONSE
This is crucial during the early phase of host defence against infection by pathogens (such as bacteria and viruses), before the antigen-specific, adaptive immune response is induced.
- LIPID RAFTS
Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane.
- TRANSACTIVATION DOMAIN
A domain that is present within a transcription factor that enables the transcription factor to interact with proteins that are involved in binding RNA-polymerase to DNA in a sequence-specific manner.
(Nuclear factor of κB). A widely expressed transcription factor that is activated by cellular stress and can induce the expression of numerous anti-apoptotic genes.
- COILED-COIL DOMAINS
A protein domain that forms a bundle of two or three α-helices. Short coiled-coil domains are involved in protein interactions, whereas long coiled-coil domains forming long rods occur in structural or motor proteins.
A term that describes cells whose nuclei have an exact multiple of the haploid set of chromosomes.
A 76-amino-acid protein that can be covalently attached to specific lysine residues in target proteins. This often forms multimeric polyubiquitin chains, which is thought to target the protein for destruction by the 26S proteasome.
Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.
- T HELPER 1/T HELPER 2
(TH1/TH2). Subsets of CD4+ T cells that are characterized by their cytokine-production profiles. TH1 cells primarily produce interferon-γ, and generally provide protection against intracellular pathogens, whereas TH2 cells mainly produce interleukin-4 (IL-4), IL-5 and IL-13, and are important for immunity to helminth parasites.
Cysteine proteases involved in apoptosis that cleave at specific aspartate residues.
The commitment and differentiation processes that lead from a haematopoietic stem cell to the production of mature cells of all lineages — erythrocytes, myeloid cells (macrophages, mast cells, neutrophils and eosinophils), B and T cells, and natural killer cells.
- RNA HELICASE
An ATP-dependent enzyme that catalyses the unwinding of RNA helices.
A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.
- ENDOTOXIC SHOCK
Also known as septic shock. This is a serious, abnormal condition that occurs when an overwhelming infection leads to low blood pressure and low blood flow. Vital organs such as the brain, heart, kidneys and liver might not function properly or might fail.
- DNA MICROARRAY
Array of polymerase chain reaction products (corresponding to either genomic or cDNA sequence) that is deposited onto solid glass slides.
Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.
- HISTONE ACETYLTRANSFERASE
(HAT). An enzyme that adds acetyl groups to histones. Many HATs function as co-activators.
A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells, that associate with DNA to form a nucleosome.
- CHROMATIN IMMUNOPRECIPITATION (ChIP) ASSAYS
ChIP assays can be used to monitor the association of DNA-binding proteins with specific promoters in vivo. Briefly, live cells are treated with crosslinking agents to tether the proteins to the DNA. The selected protein is then recovered by immunoprecipitation, the crosslinking is reversed and the co-precipitating DNA is screened for the enrichment of specific promoter fragments using the polymerase chain reaction (PCR).
- HYPOMORPHIC ALLELE
A mutant gene that has a function similar to but weaker than the wild-type gene.
Large leukocytes of the mononuclear phagocyte system found in bone marrow and the bloodstream. Monocytes are derived from pluripotent stem cells and become macrophages when they enter the tissues.
A hormone secreted by certain cells in the kidney, in response to a reduction in the amount of oxygen reaching the tissues, that stimulates red blood cell production.
A site-specific recombination system derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.
- NATURAL KILLER CELLS
(NK cells). Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they serve a broader role in host defence against invading pathogens.
- HAEMATOPOIETIC PROGENITORS
Cells that have the ability to generate all types of haematopoietic cell (multipotentiality) and to replace themselves (self-renewal) during the whole lifespan of an individual. Multipotentiality can be assessed in vitro and in vivo, whereas self-renewal can only be determined by the in vivo detection of long-term reconstitution activity.
Any of a group of RNA animal viruses that consist of naked, icosahedral 27-nm capsids with single-stranded infectious RNA (plus-strand) of 2.7 MDa.
A malignant tumour of the bone marrow.
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Levy, D., Darnell, J. STATs: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3, 651–662 (2002). https://doi.org/10.1038/nrm909
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