哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）通过感知不同环境信号，包括氨基酸，是代谢和细胞生长的中央调节因子。 GATOR2复合物是将氨基酸信号与mTORC1联系在一起的关键组成部分。在这里，我们将蛋白质精氨酸甲基转移酶1（PRMT1）确定为GATOR2的关键调节因子。在氨基酸的作用下，细胞周期依赖性激酶5（CDK5）在S307处磷酸化PRMT1以促进PRMT1从细胞核移动至细胞质和溶酶体，进而甲基化GATOR2的关键组成部分WDR24，从而激活mTORC1通路。破坏CDK5-PRMT1-WDR24轴可抑制肝细胞癌（HCC）细胞增殖和异种移植瘤生长。高PRMT1蛋白表达与HCC患者中升高的mTORC1信号相关。因此，我们的研究解析了一种磷酸化和精氨酸甲基化依赖的mTORC1激活和肿瘤生长的调节机制，并为靶向这条通路进行癌症治疗提供了分子基础。版权所有© 2023作者。由爱思唯尔公司出版。保留所有权利。

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation and xenograft tumor growth. High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.