Editors' ChoiceCell Biology

Arginine Methylation Derepresses BMP Signaling

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Sci. Signal.  16 Jul 2013:
Vol. 6, Issue 284, pp. ec159
DOI: 10.1126/scisignal.2004510

Bone morphogenetic proteins (BMPs) are secreted proteins of the transforming growth factor–β family that function through two receptor serine and threonine kinases (BMPRI and -RII) to direct morphogenesis and development (see commentary by Guo and Wang). BMPs bind to BMPRII, which phosphorylates and activates BMPRI, which in turn phosphorylates the effector proteins Smad1 and Smad5. These Smads are then recruited to BMPRI, where they associate with Smad4 to form a trimeric complex that translocates to the nucleus to activate target gene expression. Smad6 competes with Smad1 and Smad5 for binding to BMPRI as part of a feedback mechanism to inhibit signaling. Noting that phosphorylation of effector Smads in response to BMPR activation is slower than phosphorylation of substrates of receptor tyrosine kinases, Xu et al. investigated whether additional steps before Smad phosphorylation were required for BMP signaling. The authors found that knockdown of protein arginine methyltransferase 1 (PRMT1) in various human cell lines inhibited BMP4-dependent phosphorylation of Smad1 and Smad5, nuclear translocation of Smad1, and expression of BMP target genes. Coimmunoprecipitation studies showed that PRMT1 associated with Smad6, but not the other Smads, and in vitro assays showed that PRMT1 methylated Smad6 primarily on Arg74. In cells, BMP4 stimulated a transient association between PRMT1 and Smad6 that resulted in the methylation of Smad6 with faster kinetics than that of the BMP-induced phosphorylation of Smad1 and Smad5. Further analysis of protein-protein interactions showed that Smad6 associated with BMPRI and PRMT1 associated with BMPRII in unstimulated cells. BMP4 stimulated the association of BMPRI and BMPRII, bringing PRMT1 close to Smad6, which resulted in arginine methylation of Smad6, its dissociation from BMPRI, and its increased association with BMPRII. Experiments in Drosophila cells showed that the PRMT1 ortholog Dart1 methylated the Smad6 ortholog Dad, and Dart1 antagonized the effects of Dad in wing development. Together, these data suggest that the BMP-dependent arginine methylation of Smad6 by PRMT1 derepresses BMP signaling by enabling the phosphorylation and activation of Smad1 and Smad5.

J. Xu, A. H. Wang, J. Oses-Prieto, K. Makhijani, Y. Katsuno, M. Pei, L. Yan, Y. G. Zheng, A. Burlingame, K. Brückner, R. Derynck, Arginine methylation initiates BMP-induced Smad signaling. Mol. Cell 51, 5–19 (2013). [PubMed]

X. Guo, X.-F. Wang, A P(E)RM(I)T for BMP signaling. Mol. Cell 51, 1–2 (2013). [Online Journal]