PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis

Shasha Yin, Liu Liu, Charles Brobbey, Viswanathan Palanisamy, Lauren E. Ball, Shaun K. Olsen, Michael C. Ostrowski and Wenjian Gan ()
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Shasha Yin: Hollings Cancer Center, Medical University of South Carolina
Liu Liu: Hollings Cancer Center, Medical University of South Carolina
Charles Brobbey: Hollings Cancer Center, Medical University of South Carolina
Viswanathan Palanisamy: Hollings Cancer Center, Medical University of South Carolina
Lauren E. Ball: Medical University of South Carolina
Shaun K. Olsen: University of Texas Health Science Center at San Antonio
Michael C. Ostrowski: Hollings Cancer Center, Medical University of South Carolina
Wenjian Gan: Hollings Cancer Center, Medical University of South Carolina

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function.

Date: 2021
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DOI: 10.1038/s41467-021-23833-2

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