Cell growth is positively controlled by the phosphoinositide 3-kinase (PI3K)-target of rapamycin (TOR) signaling pathway under conditions of abundant growth factors and nutrients. To discover additional mechanisms that regulate cell growth, here we performed RNAi-based mosaic analyses in the Drosophila fat body, the primary metabolic organ in the fly. Unexpectedly, the knockdown of the Drosophila von Hippel-Lindau (VHL) gene markedly decreased cell size and body size. These cell growth phenotypes induced by VHL loss of function were recovered by activation of TOR signaling in Drosophila Consistent with the genetic interactions between VHL and the signaling components of PI3K-TOR pathway in Drosophila, we observed that VHL loss of function in mammalian cells causes decreased phosphorylation of ribosomal protein S6 kinase and Akt, which represent the main activities of this pathway. We further demonstrate that VHL activates TOR signaling by directly interacting with the p110 catalytic subunit of PI3K. On the basis of the evolutionarily conserved regulation of PI3K-TOR signaling by VHL observed here, we propose that VHL plays an important role in the regulation and maintenance of proper cell growth in metazoans.

中文翻译：

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Von Hippel-Lindau肿瘤抑制因子（VHL）通过与磷酸肌醇3激酶（PI3K）相互作用来刺激TOR信号传导。

雷帕霉素（TOR）信号转导途径的磷酸肌醇3-激酶（PI3K）-靶标在丰富的生长因子和营养素条件下积极控制细胞的生长。为了发现调节细胞生长的其他机制，我们在果蝇的脂肪体内（果蝇的主要代谢器官）进行了基于RNAi的镶嵌分析。出乎意料的是，果蝇von Hippel-Lindau（VHL）基因的敲低显着降低了细胞大小和体型。通过激活果蝇中的TOR信号来恢复由VHL功能丧失引起的这些细胞生长表型。与果蝇中VHL和PI3K-TOR通路的信号成分之间的遗传相互作用相一致，我们观察到哺乳动物细胞中VHL功能丧失的原因减少了。核糖体蛋白S6激酶和Akt的磷酸化 代表了这一途径的主要活动。我们进一步证明，VHL通过与PI3K的p110催化亚基直接相互作用来激活TOR信号传导。基于此处观察到的VHL对PI3K-TOR信号的进化保守调节，我们建议VHL在后生动物的正常细胞生长的调节和维持中起重要作用。