STATs: transcriptional control and biological impact View Full Text


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Article Info

DATE

2002-09-01

AUTHORS

David E. Levy, J. E. Darnell

ABSTRACT

Key PointsSignal 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. More... »

PAGES

651-662

References to SciGraph publications

  • 2001-05. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity in NATURE GENETICS
  • 1980-10. Mutations affecting segment number and polarity in Drosophila in NATURE
  • 2001-04-26. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity in NATURE
  • 2002-05-13. JAKs, STATs and Src kinases in hematopoiesis in ONCOGENE
  • 1996-10. Functional interactions between Stat5 and the glucocorticoid receptor in NATURE
  • 2001-05. A weak signal for strong responses: interferon-alpha/beta revisited in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 1998-07. Three-dimensional structure of the Stat3β homodimer bound to DNA in NATURE
  • 2002-01-21. IFN-Stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff in NATURE CELL BIOLOGY
  • 2001-05-01. Oncogenic kinase signalling in NATURE
  • 2000-05-25. Serine phosphorylation of STATs in ONCOGENE
  • 2000-05-25. Modulation of STAT signaling by STAT-interacting proteins in ONCOGENE
  • 1997-06. A new protein containing an SH2 domain that inhibits JAK kinases in NATURE
  • 2000-05-25. The roles of the Drosophila JAK/STAT pathway in ONCOGENE
  • 2000-05-25. Roles of STAT3 defined by tissue-specific gene targeting in ONCOGENE
  • 2000-05-25. STAT signaling in head and neck cancer in ONCOGENE
  • 1997-06. Structure and function of a new STAT-induced STAT inhibitor in NATURE
  • 2000-04-20. Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity in ONCOGENE
  • 1995-05. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor in NATURE
  • 2000-05-25. STATs in oncogenesis in ONCOGENE
  • 2000-05-25. Complex roles of Stat1 in regulating gene expression in ONCOGENE
  • Journal

    TITLE

    Nature Reviews Molecular Cell Biology

    ISSUE

    9

    VOLUME

    3

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrm909

    DOI

    http://dx.doi.org/10.1038/nrm909

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/12209125


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    42 schema:description Key PointsSignal 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.
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