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.
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.
McGuire
T F
TF
University of Pittsburgh, School of Medicine, Department of Pharmacology, Pennsylvania 15261, USA.
Qian
Y
Y
Blaskovich
M A
MA
Fossum
R D
RD
Sun
J
J
Marlowe
T
T
Corey
S J
SJ
Wathen
S P
SP
Vogt
A
A
Hamilton
A D
AD
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases; D000818:Animals; D004261:DNA Replication; D004789:Enzyme Activation; D051231:Farnesyltranstransferase; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014166:Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
C095583:FTI 244; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D014443:Tyrosine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017479:Receptors, Platelet-Derived Growth Factor; D018631:ras Proteins