Abstract
Mutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease. TSC2 interacts with tuberous sclerosis complex 1 to form a complex that negatively regulates cell growth and proliferation via the inactivation of mechanistic target of rapamycin complex 1. The activity of TSC2 is mainly regulated via posttranslational modifications such as phosphorylation. However, the control of TSC2 activity is not entirely achieved by phosphorylation. In this study, we show that TSC2 is methylated at R1457 and R1459 by protein arginine methyltransferase 1 (PRMT1). Methylation of these two residues can affect the phosphorylation status through protein kinase B (Akt) of TSC2 at T1462 and is essential for TSC2 stability. Taken together, these findings indicate that novel posttranslational modifications are important for the regulation of TSC2 stability through PRMT1-mediated methylation.
Highlights
Mutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease
TSC2 is expressed in lysosomes, where it interacts with tuberous sclerosis complex 1 (TSC1) to form a complex that has Rheb GTPase-activating protein (GAP) activity that negatively regulates cell growth through the inactivation of its mechanistic target, mechanistic target of rapamycin complex 13
We report that protein arginine methyltransferase 1 (PRMT1) methylates TSC2 at R1457 and R1459
Summary
Mutations in genes that encode components of tuberous sclerosis complex 2 (TSC2) are associated with tuberous sclerosis complex disease. We show that TSC2 is methylated at R1457 and R1459 by protein arginine methyltransferase 1 (PRMT1) Methylation of these two residues can affect the phosphorylation status through protein kinase B (Akt) of TSC2 at T1462 and is essential for TSC2 stability. Taken together, these findings indicate that novel posttranslational modifications are important for the regulation of TSC2 stability through PRMT1-mediated methylation. TSC2 activity is regulated by insulin signalling 7, energy stress [8,9], oxygen pathways, and growth factors 3, which all inactivate TSC2 by promoting posttranslational modifications such as phosphorylation. The methylation status of the TSC2 protein inhibits phosphorylation at T1462, leading to the regulation of its stability
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