Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation

Terence F. McGuire, Yimin Qian, Andreas Vogt, Andrew Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

We have used specific inhibitors for farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) I as well as combinations of lovastatin with geranylgeraniol (GGOH) or farnesol (FOH) to investigate the role of protein prenylation in platelet-derived growth factor (PDGF)-induced PDGF receptor tyrosine phosphorylation. NIH-3T3 cells treated with the highly specific FTase inhibitor FTI-277 had no effect on PDGF receptor tyrosine phosphorylation or PDGF activation of mitogen-activated protein kinase (MAPK) at doses that completely inhibit FTase-dependent processing. In contrast, treatment of these cells with GGTase I inhibitor GGTI-298 strongly inhibited receptor tyrosine phosphorylation, and co-treatment with FTI-277 had no additional effect. Interestingly, the inhibitory effect of GGTI-298 on PDGF activation of MAPK was only partial. Furthermore, although lovastatin, which inhibits both protein geranylgeranylation and protein farnesylation, blocked PDGF receptor tyrosine phosphorylation, co-treatment with GGOH, but not FOH, reversed the lovastatin block. In addition, although lovastatin was observed to block MAPK activation by PDGF, co-treatment with GGOH, but not FOH, restored its activation. Further investigations indicated that inhibition of receptor tyrosine phosphorylation was not due to decreased expression of the receptor or to inhibition of GGTase II. Thus, these results demonstrate that PDGF receptor tyrosine phosphorylation requires protein geranylgeranylation but not protein farnesylation and that the tyrosine phosphorylation levels of the receptor are modulated by a protein that is a substrate for GGTase I.

Original languageEnglish (US)
Pages (from-to)27402-27407
Number of pages6
JournalJournal of Biological Chemistry
Volume271
Issue number44
DOIs
StatePublished - 1996

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Protein Prenylation
Prenylation
Platelet-Derived Growth Factor Receptors
Phosphorylation
Tyrosine
Lovastatin
Platelet-Derived Growth Factor
Farnesyltranstransferase
Mitogen-Activated Protein Kinases
Chemical activation
Proteins
Farnesol
NIH 3T3 Cells
Cells
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation. / McGuire, Terence F.; Qian, Yimin; Vogt, Andreas; Hamilton, Andrew; Sebti, Saïd M.

In: Journal of Biological Chemistry, Vol. 271, No. 44, 1996, p. 27402-27407.

Research output: Contribution to journalArticle

McGuire, Terence F. ; Qian, Yimin ; Vogt, Andreas ; Hamilton, Andrew ; Sebti, Saïd M. / Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 44. pp. 27402-27407.
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