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Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in

Pablo Rodriguez-Viciana1, Crista Collins, Mike Fried

  • 1Cancer Research Institute, University of California, San Francisco, CA 94143-1028, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 13, 2006
PubMed

Insights

Polyoma virus small T-antigen (PyST) and a middle T-antigen mutant (MTA) activate the Raf-MEK-ERK pathway via protein phosphatase 2A (PP2A). This highlights a novel PP2A role in MAP kinase cascade stimulation.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Polyoma virus middle T-antigen (PyMT) activates the Raf-MEK-ERK (MAP) kinase cascade through Src family kinases and Shc binding.
  • A non-transforming PyMT mutant (MTA) and polyoma small T-antigen (PyST) were identified.

Purpose of the Study:

  • To investigate the mechanism by which MTA and PyST activate the MAP kinase pathway.
  • To explore the role of protein phosphatase 2A (PP2A) in PyST and MTA-mediated signaling.
  • To compare the signaling pathways activated by polyoma and SV40 small T-antigens.

Main Methods:

  • Isolation and characterization of PyMT variants.
  • Analysis of MAP kinase pathway activation.
  • Assessment of protein-protein interactions (Src, Shc).
  • Investigation of PP2A dependency and AKT phosphorylation.

Main Results:

  • MTA activates the MAP kinase pathway independently of Src and Shc.
  • PyST also activates the MAP kinase cascade.
  • Both MTA and PyST-mediated MAP kinase activation are PP2A-dependent.
  • Neither MTA nor PyST induce AKT phosphorylation, unlike SV40 small T-antigen.
  • SV40 small T-antigen activates AKT phosphorylation in a PP2A-dependent manner.

Conclusions:

  • Polyoma virus small T-antigen (PyST) and MTA activate the Raf-MEK-ERK (MAP) kinase cascade through a PP2A-dependent mechanism.
  • This study reveals a novel role for PP2A in stimulating the MAP kinase cascade.
  • Polyoma and SV40 small T-antigens differentially utilize PP2A to regulate distinct growth control pathways.

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