title: Arginine Methylation Initiates BMP-Induced Smad Signaling.
abstract: 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.
authors.affiliation: Department of Cell and Tissue Biology, and Anatomy, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143-0512, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: A Hongjun
authors.initials: AH
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Oses-Prieto
authors.forename: Kalpana
authors.initials: K
authors.lastname: Makhijani
authors.forename: Yoko
authors.initials: Y
authors.lastname: Katsuno
authors.forename: Ming
authors.initials: M
authors.lastname: Pei
authors.forename: Leilei
authors.initials: L
authors.lastname: Yan
authors.forename: Y George
authors.initials: YG
authors.lastname: Zheng
authors.forename: Alma
authors.initials: A
authors.lastname: Burlingame
authors.forename: Katja
authors.initials: K
authors.lastname: Brückner
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D001120:Arginine / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008745:Methylation; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051905:Smad6 Protein / Q000032:analysis / Q000737:chemistry / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D012097:Repressor Proteins; C497802:SMAD6 protein, human; D051785:Smad Proteins; D051905:Smad6 Protein; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D052006:Bone Morphogenetic Protein Receptors, Type II