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The role of protein tyrosine phosphatase 1B in Ras signaling

Nadia Dubé1, Alan Cheng, Michel L Tremblay

  • 1McGill Cancer Centre and Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Room 715, Montreal, QC, Canada H3G 1Y6.

Proceedings of the National Academy of Sciences of the United States of America
|February 10, 2004
PubMed

Insights

Protein tyrosine phosphatase 1B (PTP1B) normally promotes Ras activity. Loss of PTP1B decreases Ras signaling and cell proliferation, explaining reduced tumor incidence in deficient mice.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein tyrosine phosphatase 1B (PTP1B) negatively regulates receptor tyrosine kinase signaling.
  • PTP1B inhibition was predicted to increase oncogenic signaling, but this is not observed.
  • The role of PTP1B in Ras signaling and cell proliferation requires further elucidation.

Purpose of the Study:

  • To investigate the role of PTP1B in regulating Ras-MAPK signaling.
  • To understand the impact of PTP1B deficiency on cell proliferation and tumorigenesis.
  • To identify novel pathways regulated by PTP1B.

Main Methods:

  • Analysis of extracellular-regulated kinase (ERK) signaling in PTP1B-deficient cells.
  • Measurement of Ras activity and cell proliferation.
  • Assessment of p120RasGAP expression and p62Dok phosphorylation.
  • Complementation studies using constitutively activated Ras.

Main Results:

  • PTP1B-deficient cells showed no significant hyperactivation of ERK signaling.
  • Decreased Ras activity and reduced proliferation were observed in PTP1B-deficient cells.
  • PTP1B deficiency led to increased p120RasGAP expression and p62Dok tyrosine phosphorylation.
  • Restoration of Ras activity rescued ERK signaling and proliferation in PTP1B-deficient cells.

Conclusions:

  • PTP1B positively regulates Ras activity through pathways distal to receptor tyrosine kinases.
  • Loss of PTP1B leads to decreased Ras signaling and proliferation.
  • This mechanism may explain the lack of increased tumor incidence in PTP1B-deficient mice.

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