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

Yuhong Shen1, Karni Schlessinger, Xuejun Zhu

  • 1Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York 10021, USA.

Molecular and Cellular Biology
|December 16, 2003
PubMed

Insights

Phosphorylation of serine 705 in Signal Transducer and Activator of Transcription 3 (STAT3) is crucial for embryonic growth. Altering serine 727 phosphorylation impacts STAT3 signaling, leading to reduced birth weight and perinatal lethality in mice.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Immunology

Background:

  • Extracellular signals activate Signal Transducer and Activator of Transcription 3 (STAT3) via tyrosine 705 phosphorylation.
  • Serine 727 phosphorylation provides supplemental STAT3 activation.
  • Complete STAT3 deletion in mice results in embryonic lethality.

Purpose of the Study:

  • To investigate the in vivo function of serine 727 phosphorylation in STAT3 signaling.
  • To generate and analyze mice with alanine substitution for serine 727 in STAT3 (SA allele).

Main Methods:

  • Generation of STAT3 SA/SA mice and STAT3 SA/- mice.
  • Assessment of embryonic fibroblast transcriptional response.
  • Evaluation of mouse viability, growth, serum insulin-like growth factor 1 (IGF-1) levels, thymocyte number, apoptosis, and liver acute phase response.

Main Results:

  • SA/SA mice showed approximately 50% reduction in transcriptional response but were viable and normal.
  • SA/- mice exhibited reduced birth weight, high perinatal lethality, and stunted growth.
  • Altered serum IGF-1 levels were observed in SA/- mice, linking STAT3 serine phosphorylation to growth.
  • SA/- survivors had decreased thymocyte counts and increased apoptosis, but a normal liver acute phase response.

Conclusions:

  • STAT3 serine 727 phosphorylation plays a critical role in embryonic and perinatal growth, partly through IGF-1 signaling.
  • Defined reductions in STAT3 transcriptional capacity can be studied using these mouse models.
  • The findings highlight the complex role of STAT3 phosphorylation in development and immune function.

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