Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt.

摘要: Forkhead box O (FOXO) transcription factors, the key regulators of cell survival, are negatively controlled through PI3K-Akt signaling pathway. Phosphorylation FOXO by Akt leads to cytoplasmic localization and subsequent degradation via ubiquitin-proteasome system. Here we show a paradigm FOXO1 regulation protein arginine methyltransferase PRMT1. PRMT1 methylated at conserved Arg248 Arg250 within consensus motif for phosphorylation; this methylation directly blocked Akt-mediated phosphorylation Ser253 in vitro vivo. Silencing small interfering RNA enhanced nuclear exclusion, polyubiquitination, proteasomal FOXO1. knockdown led decrease oxidative-stress-induced apoptosis depending on Furthermore, stable expression enzymatic inactive mutant increased resistance apoptosis, whereas effect was reversed phosphorylation-deficient Our findings predict role as an inhibitory modification against phosphorylation.