Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation
Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation
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DOI：
10.1074/jbc.271.44.27402
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发表时间：
1996-11-01
影响因子：
4.8
通讯作者：
Sebti, SM
中科院分区：
文献类型：
--
作者：
McGuire, TF;Qian, YM;Sebti, SM
我们使用了法尼基转移酶（FTase）和香叶基转移酶（GGTase） I的特异性抑制剂，以及洛伐他汀与香叶基香叶醇（GGOH）或法尼醇（for）的组合来研究蛋白质戊烯酰化在血小板衍生生长因子（PDGF）诱导的PDGF受体酪氨酸磷酸化中的作用。用高度特异性FTase抑制剂FTI-277处理的NIH-3T3细胞在完全抑制FTase依赖性加工的剂量下，对PDGF受体酪氨酸磷酸化或PDGF活化的丝裂原活化蛋白激酶（MAPK）没有影响。相反，GGTase I抑制剂GGTI-298强烈抑制受体酪氨酸磷酸化，与FTI-277共处理没有额外的作用，有趣的是，GGTI-298对PDGF活化MAPK的抑制作用只是部分的。此外，尽管抑制蛋白香叶酰化和蛋白法尼化的洛伐他汀阻断了PDGF受体酪氨酸磷酸化，但与GGOH共处理，但FOH逆转了洛伐他汀阻断作用。此外，虽然观察到洛伐他汀可以阻断PDGF对MAPK的激活，但与GGOH而不是FOH共处理会阻碍其激活，进一步的研究表明，对受体酪氨酸磷酸化的抑制是印迹的：因此，这些结果表明，PDGF受体酪氨酸磷酸化需要蛋白香叶基化而不是蛋白法尼化，并且该受体的酪氨酸磷酸化水平由作为GGTase I底物的蛋白质调节。
We have used specific inhibitors for farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) I as well as combinations of lovastatin with geranylgeraniol (GGOH) or farnesol (FOR) 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 mat FOH, reversed the lovastatin block, In addition, although lovastatin was observed to block MAPK activation by PDGF, co-treatment with GGOH, but not FOH, Pestered its activation, Further investigations indicated that inhibition of receptor tyrosine phosphorylation was blot: 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.