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Regulation of Ras Localization and Cell Transformation by Evolutionarily Conserved Palmitoyltransferases

机译：进化保守的棕榈酰转移酶对Ras定位和细胞转化的调控。

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Ras can act on the plasma membrane (PM) to mediate extracellular signaling and tumorigenesis. To identify key components controlling Ras PM localization, we performed an unbiased screen to seek Schizosaccharomyces pombe mutants with reduced PM Ras. Five mutants were found with mutations affecting the same gene, S. pombe erf2 (sp-erf2), encoding sp-Erf2, a palmitoyltransferase, with various activities. sp-Erf2 localizes to the trans-Golgi compartment, a process which is mediated by its third transmembrane domain and the Erf4 cofactor. In fission yeast, the human ortholog zDHHC9 rescues the phenotypes of sp-erf2 null cells. In contrast, expressing zDHHC14, another sp-Erf2-like human protein, did not rescue Ras1 mislocalization in these cells. Importantly, ZDHHC9 is widely overexpressed in cancers. Overexpressing ZDHHC9 promotes, while repressing it diminishes, Ras PM localization and transformation of mammalian cells. These data strongly demonstrate that sp-Erf2/zDHHC9 palmitoylates Ras proteins in a highly selective manner in the trans-Golgi compartment to facilitate PM targeting via the trans-Golgi network, a role that is most certainly critical for Ras-driven tumorigenesis.
机译：Ras可以在质膜（PM）上介导细胞外信号传导和肿瘤发生。为了确定控制Ras PM定位的关键成分，我们进行了无偏筛选，以寻找PM Ras降低的裂殖酵母。发现了五个突变体，这些突变体具有影响同一基因的S. pombe erf2 （ sp-erf2 ），它们编码棕榈酸转移酶sp-Erf2，具有多种活性。 sp-Erf2定位于 trans -高尔基体区隔，该过程由其第三个跨膜结构域和Erf4辅助因子介导。在裂变酵母中，人类直系同源物zDHHC9拯救了 sp-erf2 空细胞的表型。相比之下，表达zDHHC14，另一种类似sp-Erf2的人类蛋白质，则不能挽救Ras1在这些细胞中的错位。重要的是， ZDHHC9 在癌症中广泛过表达。过表达 ZDHHC9 会促进，而抑制过表达则减少Ras PM的定位和哺乳动物细胞的转化。这些数据有力地证明，sp-Erf2 / zDHHC9在 trans -高尔基体中以高度选择性的方式将Ras蛋白棕榈酸酯化，以促进通过 trans -Golgi网络进行PM靶向。对Ras驱动的肿瘤发生至关重要的作用。

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