Regulation of RAS by ubiquitination The protein LZTR1 is mutated in human cancers and developmental diseases. Work from two groups now converges to implicate the protein in regulating signaling by the small guanosine triphosphatase RAS. Steklov et al. showed that mice haploinsufficient for LZTR1 recapitulated aspects of the human disease Noonan syndrome. Their biochemical studies showed that LZTR1 associated with RAS. LZTR1 appears to function as an adaptor that promotes ubiquitination of RAS, thus inhibiting its signaling functions. Bigenzahn et al. found LZTR1 in a screen for proteins whose absence led to resistance to the tyrosine kinase inhibitors used to treat cancers caused by the BCR-ABL oncogene product. Their biochemical studies and genetic studies in fruitflies also showed that loss of LZTR1 led to increased activity of RAS and signaling through the mitogen-activated protein kinase pathway. Science, this issue p. 1177, p. 1171 Altered ubiquitination of RAS GTPases is implicated in human diseases. The leucine zipper–like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

中文翻译：

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LZTR1 突变通过失调 RAS 泛素化驱动人类疾病

通过泛素化调节 RAS 蛋白质 LZTR1 在人类癌症和发育疾病中发生突变。来自两个小组的工作现在汇集到暗示蛋白质在调节小鸟苷三磷酸酶 RAS 的信号传导中。斯特克洛夫等人。表明 LZTR1 单倍体不足的小鼠概括了人类疾病 Noonan 综合征的各个方面。他们的生化研究表明 LZTR1 与 RAS 相关。LZTR1 似乎起到促进 RAS 泛素化的适配器的作用，从而抑制其信号功能。Bigenzahn 等人。在筛选蛋白质时发现 LZTR1，这些蛋白质的缺失导致对用于治疗由 BCR-ABL 致癌基因产物引起的癌症的酪氨酸激酶抑制剂产生抗性。他们对果蝇的生化研究和遗传研究还表明，LZTR1 的缺失导致 RAS 活性和通过丝裂原活化蛋白激酶途径的信号传导增加。科学，这个问题 p。1177 页。1171 RAS GTP 酶泛素化的改变与人类疾病有关。亮氨酸拉链样转录调节因子 1 (LZTR1) 蛋白是 cullin 3 (CUL3) 泛素连接酶复合物的接头，与人类疾病有关，但其作用机制仍然未知。我们发现小鼠中的 Lztr1 单倍体不足重现了 Noonan 综合征表型，而雪旺细胞中的 LZTR1 缺失会导致去分化和增殖。通过从完整的哺乳动物细胞中捕获 LZTR1 复合物，我们将鸟苷三磷酸酶 RAS 鉴定为 LZTR1-CUL3 复合物的底物。泛素分析表明，Lztr1 的缺失消除了赖氨酸 170 处的 Ras 泛素化。LZTR1 介导的泛素化通过减弱其与膜的关联来抑制 RAS 信号传导。疾病相关的 LZTR1 突变破坏了 LZTR1-CUL3 复合物的形成或其与 RAS 蛋白的相互作用。LZTR1 介导的泛素化对 RAS 的调节为 LZTR1 在人类疾病中的作用提供了解释。