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Cited by 200Cytokine Signaling Pathways and InteractionsGrowth Hormone and Insulin-like Growth FactorsNF-κB Signaling Pathways

Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation

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Shen, Yuhong, Schlessinger, Karni, Zhu, Xuejun, Meffre, Eric, Quimby, Fred, Levy, David E., Darnell, J. E.·2004·Molecular and Cellular Biology
DOI 10.1128/mcb.24.1.407-419.2004PMC PMC303338
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Abstract

A large number of extracellular polypeptides bound to their cognate receptors activate the transcription factor STAT3 by phosphorylation of tyrosine 705. Supplemental activation occurs when serine 727 is also phosphorylated. STAT3 deletion in mice leads to embryonic lethality. We have produced mice with alanine substituted for serine 727 in STAT3 (the SA allele) to examine the function of serine 727 phosphorylation in vivo. Embryonic fibroblasts from SA/SA mice had approximately 50% of the transcriptional response of wild-type cells. However, SA/SA mice were viable and grossly normal. STAT3 wild-type/null (+/-) animals were also normal and were interbred with SA/SA mice to study SA/- mice. The SA/- mice progressed through gestation, showing 10 to 15% reduced birth weight, three-fourths died soon after birth, and the SA/- survivors reached only 50 to 60% of normal size at 1 week of age. The lethality and decreased growth were accompanied by altered insulin-like growth factor 1 (IGF-1) levels in serum, establishing a role for the STAT3 serine phosphorylation acting through IGF-1 in embryonic and perinatal growth. The SA/- survivors have decreased thymocyte number associated with increased apoptosis, but unexpectedly normal STAT3-dependent liver acute phase response. These animals offer the opportunity to study defined reductions in the transcriptional capacity of a widely used signaling pathway.

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  • Generally, S727 phosphorylation is suggested to work with Y705 phosphorylation to activate STAT3-mediated transcription, most likely through recruiting coactivator proteins.

    “Generally, pS is suggested to work with pY to activate STAT3-mediated transcription (Wen et al., 1995; Abe et al., 2001; Shen et al., 2004) most likely through recruiting coactivator proteins (Schuringa et al., 2001; Lufei et al., 2007; Lee et al., 2009a), e.g., JNK1/2-mediated pS-STAT3 following UVA irradiation, enhanced STAT3–DNA binding in epidermal JB6 cells (Zhang et al., 2001; Liu et al., 2”

    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 Shen et al., 2004

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References 52 · Cited by 200

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Authors
Shen, Y., Schlessinger, K., Zhu, X., Meffre, E., Quimby, F., Levy, D. E., & Darnell, J. E.
Affiliations
  • Laboratory of Molecular Cell Biology
  • New York University (US)
  • Laboratory of Molecular Immunology
  • Rockefeller University (US)
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2004-01-01
Volume
24
Issue
1
Pages
407-419
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.24.1.407-419.2004
PMC
PMC303338
OpenAlex
W2153050742
Cited by
200
References
52
Citations by year
2026: 2 · 2025: 4 · 2024: 11 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 10 · 2013: 10 · 2012: 6
FWCI
4.51
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R37AI034420, AI 34420, R01AI032489, AI32489)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
STAT3, serine 727 phosphorylation, tyrosine 705 phosphorylation, postnatal survival, growth, insulin-like growth factor I, thymocyte apoptosis, acute phase response, embryonic fibroblasts, transcriptional activity
MeSH terms
Animals, DNA-Binding Proteins, Fibroblasts, Genes, Lethal, Genes, Recessive, Insulin-Like Growth Factor I, Mutation, Phosphorylation, Serine, Thymus Gland, Transcription, Genetic, Trans-Activators, STAT3 Transcription Factor, Mice

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