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Published on: July 17, 2020

Regulation of platelet-derived growth factor signaling by activated p21Ras

L L Stice1, C Vaziri, D V Faller

  • 1Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.

Frontiers in Bioscience : a Journal and Virtual Library
|January 16, 1999
PubMed

Insights

Oncogenic Ras proteins disrupt platelet-derived growth factor-beta receptor (PDGF-betaR) signaling through transcriptional downregulation and membrane-associated inhibition. Restoring normal cell growth also restores PDGF-betaR function, linking Ras, cytoskeleton, and receptor tyrosine kinases.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Oncogenesis

Background:

  • Cellular transformation involves subversion of growth control signaling pathways by oncogenes.
  • Platelet-derived growth factor-beta receptor (PDGF-betaR) signaling is crucial for mesenchymal cell growth regulation.
  • Oncogenic p21Ras proteins significantly impact PDGF-betaR signaling pathways.

Purpose of the Study:

  • To elucidate how transforming p21Ras affects PDGF-betaR signaling.
  • To identify molecular mechanisms underlying defective PDGF-betaR signaling in Ras-transformed cells.
  • To explore the link between cell morphology, cytoskeleton, and PDGF-betaR activity.

Main Methods:

  • Analysis of PDGF-betaR expression levels (mRNA and binding sites) in cells with activated p21Ras.
  • Investigation of membrane-associated factors inhibiting PDGF-betaR phosphorylation.
  • Assessment of PDGF-betaR kinase activity and function following reversion of transformed phenotype or cytoskeletal disruption.

Main Results:

  • Activated p21Ras leads to transcriptional downregulation of PDGF-betaR expression.
  • A membrane-associated factor induced by oncogenic p21Ras inhibits ligand-induced PDGF-betaR phosphorylation.
  • Disruption of the actin cytoskeleton in fibroblasts impairs PDGF-betaR function, while reversion of transformation restores it.

Conclusions:

  • Two mechanisms, transcriptional repression and membrane-associated inhibition, explain defective PDGF-betaR signaling by p21Ras.
  • Cell morphology and cytoskeletal organization are mechanistically linked to PDGF-betaR activity.
  • These findings establish a connection between cytoskeleton, Ras proteins, and receptor tyrosine kinase function.

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