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

Shasha Yin1, Liu Liu1, Lauren E Ball2

  • 1Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.

Cell Reports
|March 30, 2023
PubMed

Insights

Protein arginine methyltransferase 1 (PRMT1) regulates the GATOR2 complex and mTORC1 signaling. Targeting the CDK5-PRMT1-WDR24 pathway inhibits hepatocellular carcinoma cell growth and tumor progression.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism.
  • The GATOR2 complex links amino acid availability to mTORC1.
  • Dysregulated mTORC1 signaling contributes to cancer development.

Purpose of the Study:

  • To identify novel regulators of the GATOR2 complex and mTORC1 signaling.
  • To elucidate the molecular mechanism linking amino acid sensing to mTORC1 activation.
  • To investigate the therapeutic potential of targeting this pathway in hepatocellular carcinoma (HCC).

Main Methods:

  • Protein interaction studies
  • Phosphorylation and methylation assays
  • Cell proliferation assays
  • Xenograft tumor models
  • Analysis of patient HCC samples

Main Results:

  • Protein arginine methyltransferase 1 (PRMT1) was identified as a key regulator of GATOR2.
  • Cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1, promoting its translocation and subsequent methylation of WDR24.
  • This CDK5-PRMT1-WDR24 axis activates mTORC1 signaling.
  • Disrupting this axis suppressed HCC cell proliferation and tumor growth.
  • High PRMT1 expression correlated with elevated mTORC1 signaling in HCC patients.

Conclusions:

  • A novel regulatory mechanism involving phosphorylation and arginine methylation controls mTORC1 activation.
  • The CDK5-PRMT1-WDR24 pathway is crucial for HCC cell growth.
  • Targeting this pathway offers a potential therapeutic strategy for hepatocellular carcinoma.
Keywords:
CDK5CP: CancerCP: Molecular biologyGATOR2HCCPRMT1WDR24amino acidsarginine methylationmTORC1

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