Calcium‐dependent methylation by PRMT1 promotes erythroid differentiation through the p38α MAPK pathway

Protein arginine methyltransferase 1 (PRMT1) stimulates erythroid differentiation, but the signaling events upstream are yet to be identified. Ca(2+) plays crucial roles during erythroid differentiation. Here, we show that Ca(2+) enhances methylation during induced erythroid differentiation and that Ca(2+) directly upregulates the catalytic activity of recombinant PRMT1 by increasing Vmax toward the substrate heterogeneous nuclear ribonucleoprotein A2. We demonstrate that PRMT1 is essential and responsible for the effect of Ca(2+) on differentiation. Depletion of Ca(2+) suppresses PRMT1-mediated activation of p38alpha and p38alpha-stimulated differentiation. Furthermore, Ca(2+) stimulates methylation of p38alpha by PRMT1. This study uncovers a novel regulatory mechanism for PRMT1 by Ca(2+) and identifies the PRMT1/p38alpha axis as an intracellular mediator of Ca(2+) signaling during erythroid differentiation.