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.
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.
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CAAX 肽模拟物 FTI-244 降低血小板衍生生长因子受体酪氨酸磷酸化水平，并抑制磷脂酰肌醇 3-激酶的刺激，但不抑制丝裂原激活的蛋白激酶。
DOI：
10.1006/bbrc.1995.2287
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发表时间：
1995
影响因子：
3.1
通讯作者：
Hamilton,AD
中科院分区：
文献类型：
--
作者：
McGuire,TF;Qian,Y;Blaskovich,MA;Fossum,RD;Sun,J;Marlowe,T;Corey,SJ;Wathen,SP;Vogt,A;Hamilton,AD
Ras羧基末端四肽CAAX基序（其中C=半胱氨酸，A=亮氨酸、异亮氨酸或缬氨酸，X=甲硫氨酸或丝氨酸）的半胱氨酸法尼基化是Ras生物活性所需的。在这份报告中，我们描述了抑制剂法尼基转移酶（FTase），负责这种脂质修饰的酶，对血小板衍生生长因子（PDGF）信号在NIH-3 T3细胞的影响。在体外，CAAX肽模拟物FTI-232表现出对FTase活性的有效抑制（IC 50 =150 nM），其羧基甲基化对应物FTI-244在体内抑制Ras加工。用FTI-244处理NIH-3 T3细胞抑制PDGF诱导的DNA合成，但不刺激丝裂原活化蛋白激酶（MAPK）。然而，FTI-244显著降低PDGF诱导的PDGF受体（PDGFR）的酪氨酸磷酸化水平及其与磷脂酰肌醇-3-激酶（PI-3-K）的相关性和激活，PI-3-K是PDGF诱导的有丝分裂中的关键酶。
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.