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Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and

A Woetmann1, M Nielsen, S T Christensen

  • 1Institute of Medical Microbiology and Immunology, University of Copenhagen, DK2200 Copenhagen, Denmark.

Proceedings of the National Academy of Sciences of the United States of America
|September 15, 1999
PubMed

Insights

Protein phosphatase 2A (PP2A) regulates Signal Transducers and Activators of Transcription 3 (STAT3) phosphorylation and localization in T cells. PP2A inhibition impacts STAT3 activity, suggesting a balance between kinases and phosphatases in T cell signaling.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Signal transducers and activators of transcription (STATs) are crucial for cellular responses to cytokines and growth factors.
  • STATs translocate to the nucleus to regulate gene transcription, with both tyrosine and serine phosphorylation playing regulatory roles.

Purpose of the Study:

  • To investigate the role of serine/threonine phosphatases in regulating STAT3 signaling in human T cell lines.
  • To determine the specific phosphatases involved in controlling STAT3 phosphorylation and nuclear localization.

Main Methods:

  • Utilized human antigen-specific CD4(+) T cell lines and cutaneous T cell lymphoma lines with constitutively activated STAT3.
  • Employed various protein phosphatase inhibitors (calyculin A, okadaic acid, endothall thioanhydride, tautomycin, cyclosporine A) and kinase inhibitors (staurosporine, MEK, p38, PI3K inhibitors).
  • Assessed STAT3 phosphorylation (serine, threonine, tyrosine), DNA binding activity, and subcellular localization.

Main Results:

  • Inhibition of PP1/PP2A with calyculin A induced STAT3 serine/threonine phosphorylation, inhibited tyrosine phosphorylation and DNA binding, and caused nuclear-to-cytoplasmic relocation.
  • PP2A inhibitors (okadaic acid, endothall thioanhydride) mimicked these effects, while PP1 and PP2B inhibitors did not.
  • Staurosporine partially blocked calyculin A-induced STAT3 phosphorylation, indicating involvement of a staurosporine-sensitive kinase.

Conclusions:

  • Protein phosphatase 2A (PP2A) plays a critical role in regulating STAT3 phosphorylation and its subcellular distribution within T cells.
  • STAT3 phosphorylation levels are maintained by a balance between PP2A activity and that of staurosporine-sensitive kinases.

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