Sos 通过癌基因 Ras 介导的野生型 Ras 交叉激活对于肿瘤发生是必不可少的。

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.

Nat Commun. 2012;3:1168. doi: 10.1038/ncomms2173.

Mammalian cells contain three closely related ras genes, H-ras, K-ras and N-ras. Although in a given tumour type, oncogenic mutations are selectively observed in only one of the ras genes, the acquisition of the transformed phenotype has been shown to require the contribution of the normal products of the other ras genes. Here we demonstrate that oncogenic K-Ras promotes the activation of wild-type H- and N-Ras. This activation is mediated by oncogenic K-Ras-dependent allosteric stimulation of Sos and confers a growth advantage to oncogenic K-Ras harbouring cancer cells. These findings underscore the complementary functions of oncogenic and wild-type Ras in tumour cells and identify a potential new targeting strategy for Ras-driven tumours.

哺乳动物细胞含有三种密切相关的 ras 基因，即 H-ras、K-ras 和 N-ras。虽然在特定的肿瘤类型中，致癌突变仅选择性地观察到 ras 基因中的一个，但已经表明获得转化表型需要其他 ras 基因的正常产物的贡献。在这里，我们证明致癌 K-Ras 促进野生型 H-和 N-Ras 的激活。这种激活是通过致癌 K-Ras 依赖性 Sos 的变构刺激介导的，并赋予携带致癌 K-Ras 的癌细胞生长优势。这些发现强调了致癌和野生型 Ras 在肿瘤细胞中的互补功能，并确定了一种针对 Ras 驱动肿瘤的潜在新靶向策略。