CDK5-PRMT1-WDR24 Signaling Cascade Promotes MTORC1 Signaling and Tumor Growth

Authors

Shasha Yin
Liu Liu
Lauren E Ball
Yalong Wang
Mark T Bedford
Stephen A Duncan
Haizhen Wang
Wenjian Gan

Publication Date

4-25-2023

Journal

Cell Reports

Abstract

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.

Keywords

Humans, Amino Acids, Carcinoma, Hepatocellular, Cyclin-Dependent Kinase 5, Liver Neoplasms, Mechanistic Target of Rapamycin Complex 1, Protein-Arginine N-Methyltransferases, Repressor Proteins, TOR Serine-Threonine Kinases

Comments

PMID: 36995937