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 cancer drug resistance. In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.

中文翻译：

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LZTR1 是 RAS 泛素化和信号转导的调节器

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 酶泛素化的改变与癌症耐药性有关。在旨在了解慢性粒细胞白血病细胞耐药机制的遗传筛选中，cullin 3 衔接蛋白编码亮氨酸拉链样转录调节因子 1 (LZTR1) 基因的失活导致丝裂原活化蛋白激酶 (MAPK) 通路活性增强并降低对酪氨酸激酶抑制剂的敏感性。敲除果蝇 LZTR1 直向同源物 CG3711 导致 Ras 依赖性功能获得表型。内源性人类 LZTR1 与主要的 RAS 亚型相关。LZTR1 的失活导致内源性 KRAS（V-Ki-ras2 Kirsten 大鼠肉瘤病毒癌基因同源物）的泛素化减少和质膜定位增强。我们建议 LZTR1 作为 RAS 泛素化和 MAPK 通路激活的保守调节剂。由于 LZTR1 疾病突变未能恢复功能丧失表型，我们的研究结果为 LZTR1 参与各种遗传性和获得性人类疾病提供了分子基础。