Carboxyl methylation of Ras regulates membrane targeting and effector engagement

被引:38
作者
Chiu, VK
Silletti, J
Dinsell, V
Wiener, H
Loukeris, K
Ou, GM
Philips, MR
Pillinger, MH
机构
[1] New York Harbor Healthcare Syst Vet Affairs, Dept Med, New York, NY 10010 USA
[2] Hosp Joint Dis & Med Ctr, New York, NY 10003 USA
[3] NYU, Sch Med, Dept Med, New York, NY 10016 USA
[4] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
[5] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA
关键词
D O I
10.1074/jbc.M311602200
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
Post-translational modification of Ras proteins includes prenylcysteine-directed carboxyl methylation. Because Ras participates in Erk activation by epidermal growth factor (EGF), we tested whether Ras methylation regulates Erk activation. EGF stimulation of Erk was inhibited by AFC (N-acetyl-S-farnesyl-L-cysteine), an inhibitor of methylation, but not AGC (N-acetyl-S-geranyl-L-cysteine), an inactive analog of AFC. AFC inhibited Ras methylation as well as the activation of pathway enzymes between Ras and Erk but did not inhibit EGF receptor phosphorylation, confirming action at the level of Ras. Transient transfection of human prenylcysteine-directed carboxyl methyltransferase increased EGF-stimulated Erk activation. AFC but not AGC inhibited movement of transiently transfected green fluorescent protein-Ras from the cytosol to the plasma membrane of COS-1 cells and depleted green fluorescent protein-Ras from the plasma membrane in stably transfected Madin-Darby canine kidney cells, suggesting that methylation regulates Erk by ensuring proper membrane localization of Ras. However, when COS-1 cells were transfected with Ras complexed to CD8, plasma membrane localization of Ras was unaffected by AFC, yet EGF-stimulated Erk activation was inhibited by AFC. Thus, Ras methylation appears to regulate Erk activation both through the localization of Ras as well as the propagation of Ras-dependent signals.
引用
收藏
页码:7346 / 7352
页数:7
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