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

被引:18
作者
MCGUIRE, TF
QIAN, YM
BLASKOVICH, MA
FOSSUM, RD
SUN, JZ
MARLOWE, T
COREY, SJ
WATHEN, SP
VOGT, A
HAMILTON, AD
SEBTI, SM
机构
[1] UNIV PITTSBURGH,SCH MED,DEPT PHARMACOL,PITTSBURGH,PA 15261
[2] UNIV PITTSBURGH,SCH ARTS & SCI,DEPT CHEM,PITTSBURGH,PA 15261
[3] CHILDRENS HOSP PITTSBURGH,DEPT PEDIAT,PITTSBURGH,PA 15261
关键词
D O I
10.1006/bbrc.1995.2287
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cysteine farnesylation of the Pas 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 Pas 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. (C) 1995 Academic Press, Inc.
引用
收藏
页码:295 / 303
页数:9
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