Abstract
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily of multifunctional ligands that transduce their signals through type I and II serine/threonine kinase receptors and intracellular Smad proteins. Recently, we identified the glycosylphosphatidylinositol-anchored repulsive guidance molecules RGMa, DRAGON (RGMb), and hemojuvelin (RGMc) as coreceptors for BMP signaling (Babbit, J. L., Huang, F. W., Wrighting, D. W., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R., Schneyer, A., Woolf, C. J., Andrews, N. C., and Lin, H. Y. (2006) Nat. Genet. 38, 531-539; Babbit, J. L., Zhang, Y., Samad, T. A., Xia, Y., Tang, J., Schneyer, A., Woolf, C. J., and Lin, H. Y. (2005) J. Biol. Chem. 280, 29820-29827; Samad, T. A., Rebbapragada, A., Bell, E., Zhang, Y., Sidis, Y., Jeong, S. J., Campagna, J. A., Perusini, S., Fabrizio, D. A., Schneyer, A. L., Lin, H. Y., Brivanlou, A. H., Attisano, L., and Woolf, C. J. (2005) J. Biol. Chem. 280, 14122-14129). However, the mechanism by which RGM family members enhance BMP signaling remains unknown. Here, we report that RGMa bound to radiolabeled BMP2 and BMP4 with Kd values of 2.4+/-0.2 and 1.4+/-0.1 nm, respectively. In KGN human ovarian granulosa cells and mouse pulmonary artery smooth muscle cells, BMP2 and BMP4 signaling required BMP receptor type II (BMPRII), but not activin receptor type IIA (ActRIIA) or ActRIIB, based on changes in BMP signaling by small interfering RNA inhibition of receptor expression. In contrast, cells transfected with RGMa utilized both BMPRII and ActRIIA for BMP2 or BMP4 signaling. Furthermore, in BmpRII-null pulmonary artery smooth muscle cells, BMP2 and BMP4 signaling was reduced by inhibition of endogenous RGMa expression, and RGMa-mediated BMP signaling required ActRIIA expression. These findings suggest that RGMa facilitates the use of ActRIIA by endogenous BMP2 and BMP4 ligands that otherwise prefer signaling via BMPRII and that increased utilization of ActRIIA leads to generation of an enhanced BMP signal.
Highlights
Bone morphogenetic proteins (BMPs)4 are a large subfamily of the transforming growth factor- (TGF-) superfamily of multifunctional ligands that regulate cell proliferation and differentiation, chemotaxis, and apoptosis
BMP2 and BMP4 Are Both Endogenous Ligands for RGMa in KGN Cells—We demonstrated previously that RGMa-Fc binds BMP2 and BMP4, but not BMP7 and TGF-1, and that RGMamediated BMP signaling can be inhibited by an antibody against both BMP2 and BMP4 (14)
Originally discovered as glycosylphosphatidylinositol-anchored cell-surface proteins involved in neuronal differentiation and cell-cell contact in the developing nervous system (16 –18), it is clear that repulsive guidance molecule (RGM) family members are coreceptors for BMP signaling (13–15)
Summary
Primers that have not been published elsewhere are shown. h, human; m, mouse. Accession no. We have shown recently that the repulsive guidance molecule (RGM) family members RGMa, DRAGON (RGMb), and hemojuvelin (RGMc) are coreceptors that enhance BMP signaling (13–15). RGM family members share 50 – 60% protein sequence homology and have similar structural features, including a signal sequence, conserved proteolytic cleavage site, partial von Willebrand factor type D domain, and glycosylphosphatidylinositol anchor (16 –19). Hemojuvelin is expressed at high levels in the skeletal muscle, heart, and liver (22). It is mutated in juvenile hemochromatosis, a disorder of iron overload (23). We have obtained data suggesting that RGM proteins appear to mediate BMP signaling through the classical BMP pathway (13–15), the molecular mechanisms by which RGM family members enhance BMP signaling remain largely unknown. We found that RGMa has Kd values of 2.4 Ϯ 0.2 nM for BMP2 and 1.4 Ϯ 0.1 nM for BMP4 and that RGMa enhances BMP signaling by allowing BMP2 and BMP4 to increase their utilization of ActRIIA
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