Regulation of intracellular actin polymerization by prenylated cellular proteins.
Regulation of intracellular actin polymerization by prenylated cellular proteins.
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DOI：
10.1083/jcb.117.2.347
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发表时间：
1992-04
期刊：
影响因子：
--
通讯作者：
Smith MR
中科院分区：
文献类型：
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作者：
Fenton RG;Kung HF;Longo DL;Smith MR
翻译后修饰通过共价连接的聚异戊二烯中间体的羧基末端CAAX盒基序是必需的蛋白质，如p21 ras，超基因家族的ras相关蛋白，核纤层蛋白，和亚基的异源三聚体G蛋白的生物功能。在洛伐他汀存在下生长的细胞，其抑制HMG-CoA还原酶并阻止蛋白质异戊烯化所需的中间体的合成，形成圆形的、可触变的形态。我们的数据表明，这是由于肌动蛋白电缆的选择性损失，而没有在微管晶格或中间丝结构的总体变化。将蛋白质异戊烯基转移酶的竞争性肽抑制剂微量注射到细胞的细胞质中，诱导了与肌动蛋白电缆损失相同的形态学变化。甲羟戊酸（MVA）逆转洛伐他汀诱导的形态变化，诱导肌动蛋白电缆的快速重聚合，同时恢复到扁平形态。此外，显微注射法呢基焦磷酸或香叶基香叶基焦磷酸到洛伐他汀处理的细胞中也导致快速的形态逆转。MVA诱导的形态逆转需要血清的存在，并且不依赖于细胞外钙。在生长培养基中加入放线菌酮可以防止洛伐他汀诱导的肌动蛋白电缆的丢失，并通过一种独立于MVA的机制引起洛伐他汀处理细胞的形态学逆转。A1 F4-以与MVA难以区分的方式诱导形态学逆转。这些数据表明，异戊二烯化的蛋白质（S）在调节细胞内肌动蛋白的状态中起着关键作用，GGPP可以拯救洛伐他汀诱导的形态表型的胆固醇生物合成的上游中间体的情况下。我们已经开始剖析介导这一途径的信号事件。
Posttranslational modification by covalent attachment of polyisoprene intermediates to a carboxyterminal CAAX-box motif is required for the biologic function of proteins such as p21ras, the supergene family of ras-related proteins, nuclear lamins, and subunits of heterotrimeric G- proteins. Cells grown in the presence of lovastatin, which inhibits HMG- CoA reductase and prevents synthesis of intermediates required for protein prenylation, develop a round, refractile morphology. Our data indicate that this is due to the selective loss of actin cables without gross changes in the microtubular lattice or intermediate filament structure. Microinjection of a competitive peptide inhibitor of protein prenyltransferases into the cytoplasm of cells induces an identical change in morphology with loss of actin cables. Mevalonate (MVA) reverses the lovastatin-induced morphologic change by inducing a rapid repolymerization of actin cables with coincident reversion to the flat morphology. Furthermore, microinjection of farnesyl-pyrophosphate or geranylgeranyl-pyrophosphate into lovastatin-treated cells also results in rapid morphologic reversion. The morphologic reversion induced by MVA requires the presence of serum, and is independent of extracellular calcium. The addition of cycloheximide to the growth medium prevents lovastatin-induced loss of actin cables, and causes morphologic reversion of lovastatin-treated cells by a mechanism that is independent of MVA. A1F4- induces morphologic reversion in a manner indistinguishable from MVA. These data indicate that prenylated protein(s) play a critical role in regulating the state of intracellular actin, and that GGPP can rescue the lovastatin-induced morphologic phenotype in the absence of upstream intermediates of cholesterol biosynthesis. We have begun to dissect the signaling events that mediate this pathway.