Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins
Abstract
Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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STAT3 belongs to the family of STAT transcription factors which mediate the cellular response to a variety of cytokines and growth factors including IL-6.
“Signal transducer and activator of transcription 3 (STAT3) belongs to the family of STAT transcription factors which mediate the cellular response to a variety of cytokines and growth factors including IL-6 (6-8”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [6]
STAT1 and IRF5 are involved in M1 polarization/maintenance; STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in M2 polarization/maintenance.
“Specifically, STAT1 and IRF5 have been shown to be involved in polarization and maintenance of an M1 phenotype while STAT6, IRF4, CREB-C/EBPβ, and PPARγ are involved in polarization and maintenance of an M2 phenotype [23–30].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [23]
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“Although numerous biochemical cascades are involved in cytokine signaling, this discussion will primarily focus on 2 families of protein tyrosine kinases, termed JAKs and STATs, which uniquely function in cytokine signaling (Fig 1, A).(129,130) The role for JAK family members in the pathway to gene activation was larg…”
BackgroundPrognostic significance of autoimmunity during treatment of melanoma with interferon
Krauze, M. T., Tarhini, A. A., Gogas, H. J., & Kirkwood, J. M. (2011) · Seminars in Immunopathology · doi:10.1007/s00281-011-0247-y · Cited by 507 · see citing works
“Effects include the inhibition of viral growth, growth inhibition of tumor cells, and immunostimulatory effects by activation of different cytokines [28].”
BackgroundSilencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape
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“STAT3 can be activated by IL-6, EGFR, PDGF, leukemia inhibitory factor (LIF), oncostatin M, and the ciliary neurotrophic factor (CNTF) family of cytokines, which are all known to mediate their signal through the gp130 protein [130–133].”
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“Indeed, genetic studies revealed that U1A cells were deficient in TYK2, whereas the U4–U6 cells were eventually found to be deficient in other components of the IFNb and IFNg JAK–STAT signalling cascades (Velazquez et al. 1992; Muller et al. 1993a,b; Darnell et al. 1994).”
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“Secreted IFN-I then bind to the interferon alpha and beta receptor (IFNAR, composed of the IFNAR1 and IFNAR2 subunits), leading to the activation of the Jak tyrosine kinases tyrosine kinase 2 (Tyk2) and Janus kinase 1 (JAK1), which in turn phosphorylate the signal transducer and activator of transcription (STAT)1 and…”
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“The JAK/STAT signaling pathway comprises of the receptor and adaptor proteins of interleukin 6 (IL-6), interferon-alpha (IFN-α), and interferon-gamma (IFN-γ) that mediate pleiotropic functions upon binding to their respective ligands [1,2].”
BackgroundCytokines in the Treatment of Cancer
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“This modification allows the recruitment of various signalling molecules including members of the signal transducer and activator of transcription (STAT) family of DNA binding proteins.(7) STATs are another important Jak substrate.”
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BackgroundLeukemia inhibitory factor (LIF)
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“The STAT proteins are a family of transcription factors that are usually present in an inactive state in the cytoplasm [39].”
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The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion
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<i>STAT3</i> Plays a Critical Role in <i>KRAS</i> -Induced Pancreatic Tumorigenesis
Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., Levy, D. E., Settleman, J., Engelman, J. A., & Bardeesy, N. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0908 · Cited by 413 · see citing works
- Authors
- Darnell, J. E., Kerr, L. M., & Stark, G. R.
- Affiliations
- Rockefeller University (US)
- Case Comprehensive Cancer Center (US)
- ORCID
- Stark, George R.
- Venue
- Science
- Published
- 1994-06-03
- Volume
- 264
- Issue
- 5164
- Pages
- 1415-1421
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2029275361
- Cited by
- 6,080
- References
- 85
- Citations by year
- 2026: 84 · 2025: 139 · 2024: 175 · 2023: 170 · 2022: 183 · 2021: 177 · 2020: 162 · 2019: 155 · 2018: 121 · 2017: 166 · 2016: 148 · 2015: 152 · 2014: 160 · 2013: 207 · 2012: 188
- FWCI
- 28.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- JAK/STAT signaling, interferon-alpha, interferon-gamma, signal transduction, STAT proteins, transcriptional activation, JAK kinases, interferon receptor, nuclear translocation, DNA binding
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cell Line, DNA-Binding Proteins, Genes, Genetic Complementation Test, Humans, Interferon-gamma, Molecular Sequence Data, Mutation, Protein-Tyrosine Kinases, Regulatory Sequences, Nucleic Acid, Transcription Factors, Signal Transduction, Transcriptional Activation, Interferon-alpha, Interferon-Stimulated Gene Factor 3, Interferon-Stimulated Gene Factor 3, gamma Subunit
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