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Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling

J Gu1, M Tamura, K M Yamada

  • 1Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370, USA.

The Journal of Cell Biology
|December 2, 1998
PubMed

Insights

The tumor suppressor PTEN inhibits cell migration by blocking the extracellular signal-regulated kinase (ERK) pathway. PTEN deactivates focal adhesion kinase (FAK) and Shc phosphorylation, impacting Ras activity and cell spreading.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and regulates cell migration.
  • PTEN's role in modulating specific signaling pathways, particularly the MAPK pathway, requires further elucidation.

Purpose of the Study:

  • To investigate the effect of PTEN on the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway.
  • To determine the specific inhibitory point of PTEN within the Ras/Raf/MEK/ERK cascade.

Main Methods:

  • Expression of PTEN in glioblastoma cells lacking the protein.
  • Stimulation with fibronectin, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).
  • Analysis of Shc phosphorylation, Ras activity, and downstream MAPK components.

Main Results:

  • PTEN expression selectively inhibited integrin-mediated and growth factor-induced MAPK activation.
  • PTEN suppressed Shc phosphorylation and Ras activity, but not EGF receptor autophosphorylation.
  • The phosphatase domain of PTEN was essential for inhibiting MAPK and Ras activity.

Conclusions:

  • PTEN functions to down-regulate FAK and Shc phosphorylation, Ras activity, and downstream MAP kinase activation.
  • PTEN impacts focal contact formation and cell spreading, suggesting a broad role in regulating cell adhesion and motility.
  • PTEN's inhibitory effect on the ERK pathway is crucial for its tumor suppressor functions.

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