CDK5-PRMT1-WDR24 signaling cascade promotes mTORC1 signaling and tumor growth

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...

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Published in:Cell reports (Cambridge) 2023-04, Vol.42 (4), p.112316-112316, Article 112316
Main Authors: Yin, Shasha, Liu, Liu, Ball, Lauren E., Wang, Yalong, Bedford, Mark T., Duncan, Stephen A., Wang, Haizhen, Gan, Wenjian
Format: Article
Language:English
Subjects:
amino acids
arginine methylation
CDK5
CP: Cancer
CP: Molecular biology
GATOR2
HCC
mTORC1
PRMT1
WDR24
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Summary: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. [Display omitted] •PRMT1 is required for amino-acid-induced mTORC1 activation•CDK5 phosphorylates PRMT1 to promote its cytoplasmic localization and activity•PRMT1 methylates WDR24 to promote mTORC1 activation by amino acids•The CDK5-PRMT1-WDR24 axis is critical for cell proliferation and tumor growth Yin et al. find that CDK5 serves as an upstream kinase and WDR24 acts as a downstream target of PRMT1 to promote mTORC1 pathway activation in response to amino acids. They further show that disruption of CDK5, PRMT1, and WDR24 suppresses tumor growth, implicating their therapeutic potential.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.112316