Abstract 323: Arginine Methylation Regulates Epicardial Cell Plasticity
Kinase activation and substrate phosphorylation commonly form the backbone of signaling cascades. TGFbeta family ligands induce activation of their signaling effectors, the Smads, through C-terminal phosphorylation by transmembrane receptor kinases following type I and type II receptor complex formation. Here we show that arginine methylation, which regulates gene expression, yet also modifies some signaling mediators, initiates TGFbeta-induced Smad signaling. TGFbeta-induced receptor complex formation promotes presentation of the methyltransferase PRMT1 to the inhibitory Smad7, resulting in Smad7 methylation at a specific arginine as revealed by mass spectrometry analysis and confirmed with a mutagenesis approach. Antibodies specific for asymmetric di-methylated arginine further confirmed Smad7 methylation and Smad7 recruitment to the cell membrane upon TGFbeta stimulation. TGFbeta-induced and PRMT1-mediated Smad7 methylation leads to Smad7 dissociation from TGFbeta type I receptors, allowing activation of effector Smads through phosphorylation. This PRMT1-mediated Smad7 methylation is required in TGFbeta-regulated epicardial plasticity, as apparent by the role of PRMT1 in TGFbeta-induced epithelial-to-mesenchymal trans-differentiation and transcriptional reprogramming in mouse epicardial cells.
- © 2013 by American Heart Association, Inc.