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Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

Koichi Okumura1, Mujun Zhao, Ronald A Depinho

  • 1Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, La Jolla, CA 92093-0660, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 22, 2005
PubMed

Insights

The PTEN protein

Area of Science:

  • Oncogenic signaling and tumor suppression.
  • Molecular and cellular biology.
  • Protein-protein interactions in cancer.

Background:

  • PTEN (phosphatase and tensin homologue) is a crucial tumor suppressor.
  • The C-terminal region of PTEN is vital for protein stability and is frequently mutated in cancers.
  • The oncogenic protein MSP58 promotes cellular transformation.

Purpose of the Study:

  • To investigate the interaction between the PTEN C-terminal domain and the oncogenic MSP58 protein.
  • To determine the role of this interaction in cellular transformation.
  • To elucidate the functional significance of the PTEN C-terminal region beyond its catalytic activity.

Main Methods:

  • Co-immunoprecipitation assays to confirm physical interaction between PTEN and MSP58.
  • Cell transformation assays using mouse embryo fibroblasts (MEFs) with varying PTEN and MSP58 expression.
  • Site-directed mutagenesis to analyze the role of specific PTEN residues (e.g., Thr-366) and catalytic activity (G129R mutant).

Main Results:

  • The PTEN C-terminal domain directly interacts with the forkhead-associated domain of MSP58, requiring PTEN Thr-366.
  • Wild-type PTEN significantly inhibits MSP58-induced cellular transformation in Pten-/- MEFs.
  • A PTEN mutant (T366A) unable to interact with MSP58 failed to suppress transformation, indicating the interaction is critical.
  • A catalytically inactive PTEN mutant (G129R) retained the ability to suppress MSP58 oncogenicity, highlighting a non-catalytic function.

Conclusions:

  • The PTEN C-terminal region possesses a previously unrecognized function in suppressing cellular transformation.
  • This function is mediated through direct physical interaction with the oncogenic protein MSP58.
  • PTEN's role in cancer suppression involves both its catalytic activity and its C-terminal domain's interaction capabilities.

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