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. Ca²⁺ plays crucial roles during erythroid differentiation. Here, we show that Ca²⁺ enhances methylation during induced erythroid differentiation and that Ca²⁺ directly upregulates the catalytic activity of recombinant PRMT1 by increasing V_max toward the substrate heterogeneous nuclear ribonucleoprotein A2. We demonstrate that PRMT1 is essential and responsible for the effect of Ca²⁺ on differentiation. Depletion of Ca²⁺ suppresses PRMT1-mediated activation of p38α and p38α-stimulated differentiation. Furthermore, Ca²⁺ stimulates methylation of p38α by PRMT1. This study uncovers a novel regulatory mechanism for PRMT1 by Ca²⁺ and identifies the PRMT1/p38α axis as an intracellular mediator of Ca²⁺ signaling during erythroid differentiation.