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Cited by 150Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesReceptor Mechanisms and Signaling

The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6

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Zhang, Tong, Kee, Wei Hua, Seow, Kah Tong, Fung, Winnie, Cao, Xinmin·2000·Molecular and Cellular Biology
DOI 10.1128/mcb.20.19.7132-7139.2000PMC PMC86266
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Abstract

STAT proteins are a family of latent transcription factors that mediate the response to various cytokines and growth factors. Upon stimulation by cytokines, STAT proteins are recruited to the receptors via their SH2 domains, phosphorylated on a specific tyrosine, dimerized, and translocated into the nucleus, where they bind specific DNA sequences and activate the target gene transcription. STATs share highly conserved structures, including an N-domain, a coiled-coil domain, a DNA-binding domain, a linker domain, and an SH2 domain. To investigate the role of the coiled-coil domain, we performed a systematic deletion analysis of the N-domain and each of the alpha-helices and mutagenesis of conserved residues in the coiled-coil region of Stat3. Our results indicate that the coiled-coil domain is essential for Stat3 recruitment to the receptor and the subsequent tyrosine phosphorylation and tyrosine phosphorylation-dependent activities, such as dimer formation, nuclear translocation, and DNA binding, stimulated by epidermal growth factor (EGF) or interleukin-6 (IL-6). Single mutation of Asp170 or, to a lesser extent, Lys177 in alpha-helix 1 diminishes both receptor binding and tyrosine phosphorylation. Furthermore, the Asp170 mutant retains its ability to bind to DNA when phosphorylated on Tyr705 by Src kinase in vitro, implying a functional SH2 domain. Finally, we demonstrate a direct binding of Stat3 to the receptor. Taken together, our data reveal a novel role for the coiled-coil domain that regulates the early events in Stat3 activation and function.

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  • Previously, the R609L mutation that disrupts the SH2 domain function of STAT3 has only been made in the context of STAT3α, but its expression in cells with endogenous STAT3α levels precluded its detailed characterization of phosphorylation and nuclear translocation kinetics.

    “Previously, the R609L mutation that disrupts the SH2 domain function of STAT3 has only been made in the context of STAT3α, but its expression in cells with endogenous STAT3α levels precluded its detailed characterization of phosphorylation and nuclear translocation kinetics [29].”

    From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [29]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation.

    “Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation (Zhang et al., 2000; Mertens et al., 2015; Namanja et al., 2016).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Zhang et al., 2000

    The Results and Discussion (page not available in our copy) show that mutations in STAT3’s coiled-coil domain affect SH2-mediated receptor binding, and propose an intramolecular interaction between the domains. This supports the suggested long-range communication and possible modulation of activity. The mutations studied were experimentally introduced; the paper does not identify them as disease-causing. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Dimerization between STAT3 proteins is a prerequisite for nuclear translocation upon activation and occurs via its functional SH2 domain.

    “Dimerization between STAT3 proteins has been a prerequisite for nuclear translocation upon activation and this interaction occurs via its functional SH2 domain [28,29].”

    From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [29]

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Cited by

Sorted by citations

Authors
Zhang, T., Kee, W. H., Seow, K. T., Fung, W., & Cao, X.
Affiliations
Institute of Molecular and Cell Biology (SG)
Corresponding author
Cao, Xinmin
ORCID
Zhang, Tong
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2000-10-15
Volume
20
Issue
19
Pages
7132-7139
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.20.19.7132-7139.2000
PMC
PMC86266
OpenAlex
W2139372772
Cited by
150
References
3
Citations by year
2026: 7 · 2025: 8 · 2024: 11 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 4 · 2019: 10 · 2018: 8 · 2017: 4 · 2016: 3 · 2015: 8 · 2014: 5 · 2013: 5 · 2012: 5
FWCI
2.21
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Science Board
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
STAT3, coiled-coil domain, SH2 domain, receptor binding, tyrosine phosphorylation, epidermal growth factor, interleukin-6, protein dimerization, nuclear translocation, DNA binding, Src kinase, transcription factor activation
MeSH terms
Animals, DNA, DNA-Binding Proteins, Epidermal Growth Factor, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Glycoproteins, Neoplasm Proteins, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Recombinant Fusion Proteins, Structure-Activity Relationship, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Trans-Activators, Antigens, CD, Interleukin-6, Gene Expression Regulation, Neoplastic, Point Mutation, Protein Structure, Secondary, src Homology Domains, Dimerization, COS Cells, Receptors, Interleukin-6, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice

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