11 July, 2013 Volume 51, Issue 1

On the cover: Signaling by cell-surface receptors is commonly mediated by kinases, resulting in phosphorylation of receptors and signaling effectors. The TGF-β-related BMP ligands act as growth and differentiation factors and induce phosphorylation of “type I” by “type II” receptors and subsequent activation of intracellular Smads through phosphorylation by the type I receptor kinases. In this issue, Xu et al. (5–19) show that, in response to BMP, arginine methylation of the receptor-associated inhibitory Smad6 by PRMT1 initiates Smad activation. This methylation results in dissociation of Smad6 from the type I receptor, thus releasing the repression of Smad activation and enabling the type I receptors to activate Smad1 and Smad5 through phosphorylation. In the image, the prince outside, representing the BMP ligand, waits patiently, while the princess, representing PRMT1, unlocks the gate (i.e., the BMP receptor complex) by removing the bolt, Smad6. This then allows the doors to be opened and the ligand to activate intracellular Smad signaling. Artwork by Mofei Han.

Kinase activation and substrate phosphorylation commonly form the backbone of signaling cascades. Bone morphogenetic proteins (BMPs), a subclass of TGF-β family ligands, induce activation of their signaling effectors, the Smads, through C-terminal phosphorylation by transmembrane receptor kinases. However, the slow kinetics of Smad activation in response to BMP suggests a preceding step in the initiation of BMP signaling. We now show that arginine methylation, which is known to regulate gene expression, yet also modifies some signaling mediators, initiates BMP-induced Smad signaling. BMP-induced receptor complex formation promotes interaction of the methyltransferase PRMT1 with the inhibitory Smad6, resulting in Smad6 methylation and relocalization at the receptor, leading to activation of effector Smads through phosphorylation. PRMT1 is required for BMP-induced biological responses across species, as evidenced by the role of its ortholog Dart1 in BMP signaling during Drosophila wing development. Activation of signaling by arginine methylation may also apply to other signaling pathways.