PRMT1 methylates SKP1 to inhibit the ubiquitination of pro-proliferative phosphoproteins during hepatocyte proliferation

Protein phosphorylation cascades are essential for cell proliferation. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a key stabilizer of phosphoproteins that is indispensable for hepatocyte proliferation during liver regeneration. PRMT1 is upregulated by epidermal growth factor (EGF) via receptor tyrosine kinase signaling and catalyzes the asymmetric dimethylation (ADMA) modification of SKP1 at the R81 residue. This methylation event disrupts FBXW7 recruitment to the SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complex, thereby preventing FBXW7-mediated ubiquitination. Since FBXW7 targets multiple pro-proliferative phosphoproteins, this mechanism prevents their degradation, ensuring the transduction of proliferative signals via phosphorylation cascades. Furthermore, in vivo administration of S-adenosylmethionine, the methyl donor for PRMT-catalyzed methylation, significantly accelerates liver regeneration in both mice and patients. Collectively, these findings establish PRMT1 as a central post-translational regulator of hepatocyte proliferation, highlighting its potential as a therapeutic target for liver diseases. During liver regeneration, EGF upregulates PRMT1, leading to increased asymmetric arginine dimethylation at R81 of SKP1. This impedes the interaction between SKP1 and FBXW7, protects pro-proliferative phosphoproteins from ubiquitin-mediated degradation, and thereby maintains hepatocyte proliferation.