CAAX Peptidomimetic FTI-244 Decreases Platelet-Derived Growth Factor Receptor Tyrosine Phosphorylation Levels and Inhibits Stimulation of Phosphatidylinositol 3-Kinase but Not Mitogen-Activated Protein Kinase

Terence F. McGuire, Yimin Qian, Michelle A. Blaskovich, Renae D. Fossum, Jiazhi Sun, Tara Marlowe, Seth J. Corey, Steven P. Wathen, Andreas Vogt, Andrew D. Hamilton, Said M. Sebti

Research output: Contribution to journalArticle

Abstract

Cysteine farnesylation of the Ras carboxyl terminal tetrapeptide CAAX motif (where C=cysteine, A=leucine, isoleucine, or valine, and X=methionine or serine) is required for Ras biological activity. In this report, we describe the effects of inhibitors of farnesyltransferase (FTase), the enzyme responsible for this lipid modification, on platelet-derived growth factor (PDGF) signaling in NIH-3T3 cells. In vitro, the CAAX peptidomimetic FTI-232 exhibits potent inhibition of FTase activity (IC50=150 nM) and its carboxyl-methylated counterpart, FTI-244, inhibits Ras processing in vivo. Treatment of NIH-3T3 cells with FTI-244 inhibits PDGF-induced DNA synthesis but not stimulation of mitogen-activated protein kinase (MAPK). However, FTI-244 significantly reduces PDGF-induced tyrosine phosphorylation levels of PDGF receptor (PDGFR) as well as its association with, and activation of, phosphatidylinositol-3-kinase (PI-3-K), a key enzyme in PDGF-induced mitogenesis.

Original languageEnglish (US)
Pages (from-to)295-303
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume214
Issue number1
DOIs
StatePublished - 1995

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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