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Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity

C Lufei1, T H Koh, T Uchida

  • 1Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore.

Oncogene
|June 15, 2007
PubMed

Insights

Peptidyl-prolyl cis/trans isomerase 1 (Pin1) enhances Signal transducer and activator of transcription 3 (Stat3) activity by interacting with its Ser727 phosphorylation site. This interaction promotes Stat3-driven gene expression and epithelial-mesenchymal transition in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Signal transducer and activator of transcription 3 (Stat3) is a key transcription factor in cytokine signaling.
  • Constitutive Stat3 activation is implicated in various cancers, functioning as an oncogene.
  • Stat3 transcriptional activity is regulated by Tyr-phosphorylation, but the role of Ser727 phosphorylation remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which Ser727 phosphorylation regulates Stat3 transcriptional activity.
  • To investigate the role of peptidyl-prolyl cis/trans isomerase 1 (Pin1) in Stat3 regulation.
  • To determine Pin1's impact on Stat3-mediated gene expression and cancer cell behavior.

Main Methods:

  • Co-immunoprecipitation to assess Pin1-Stat3 interaction.
  • Overexpression and knockdown studies of Pin1 in cancer cell lines.
  • Reporter assays to measure Stat3 transcriptional activity.
  • Western blotting to detect protein phosphorylation and expression.
  • Analysis of epithelial-mesenchymal transition markers.

Main Results:

  • Pin1 interacts with Stat3 upon cytokine/growth factor stimulation, specifically dependent on Ser727 phosphorylation.
  • Pin1 overexpression enhances Stat3 transcriptional activity, target gene expression, and p300 coactivator recruitment.
  • Pin1 deficiency compromises Stat3 activity and its downstream effects.
  • Pin1 promotes Stat3-mediated epithelial-mesenchymal transition in breast cancer cells.

Conclusions:

  • Pin1 acts as a novel regulator of Stat3 transcriptional activity through a Ser727 phosphorylation-dependent mechanism.
  • Pin1 enhances Stat3 function by promoting its interaction with coactivators like p300.
  • Pin1's role in Stat3-mediated EMT highlights its potential as a therapeutic target in Stat3-driven cancers.

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