Asymmetric Dimethylation of Ribosomal S6 Kinase 2 Regulates Its Cellular Localisation and Pro-Survival Function

Ribosomal S6 kinases (S6Ks) are critical regulators of cell growth, homeostasis, and survival, with dysregulation of these kinases found to be associated with various malignancies. While S6K1 has been extensively studied, S6K2 has been neglected despite its clear involvement in cancer progression. Protein arginine methylation is a widespread post-translational modification regulating many biological processes in mammalian cells. Here, we report that p54-S6K2 is asymmetrically dimethylated at Arg-475 and Arg-477, two residues conserved amongst mammalian S6K2s and several AT-hook-containing proteins. We demonstrate that this methylation event results from the association of S6K2 with the methyltransferases PRMT1, PRMT3, and PRMT6 in vitro and in vivo and leads to nuclear the localisation of S6K2 that is essential to the pro-survival effects of this kinase to starvation-induced cell death. Taken together, our findings highlight a novel post-translational modification regulating the function of p54-S6K2 that may be particularly relevant to cancer progression where general Arg-methylation is often elevated.

Automated summary

Ribosomal S6 kinases (S6Ks) play crucial roles in cell growth, homeostasis, and survival, and dysregulation of these kinases is implicated in various malignancies. While S6K1 has been extensively studied, the involvement of S6K2 in cancer progression has been overlooked. This study reveals that p54-S6K2 undergoes asymmetric dimethylation at Arg-475 and Arg-477, mediated by methyltransferases PRMT1, PRMT3, and PRMT6. This methylation event leads to nuclear localization of S6K2, which is crucial for its pro-survival effects during starvation-induced cell death. These findings highlight a novel post-translational modification that regulates p54-S6K2 function, and its relevance in cancer progression where general arginine methylation is often elevated.