Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2007; 282(25):18129-40. DOI: 10.1074/jbc.M701679200
Source: PubMed

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.

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    • "The glycosylphosphatidylinositol (GPI) protein family members linked to repulsive molecular orientation (RGM), which includes the RGM-a, -b and -c, are co-receptors for BMP-2 and BMP-4 and reinforce the signalling of BMPs (Samad et al., 2005). Xia et al. (2007) stated that RGM-b, also known as hemojuvelin and DRAGON, respectively, interacts with BMP receptors of which type I or type II, bind to BMP-2 and BMP-4, but not BMP-7 and TGF-␤1. However, cells transfected with the RGM use both BMPRII and ActR-II for signalling BMP-2/4, suggesting that RGM facilitates the use of ActR-II by BMP-2/4. "
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    ABSTRACT: Summary The bone morphogenetic protein (BMP) family consists of several growth factor proteins that belong to the transforming growth factor-β (TGF-β) superfamily. BMPs bind to type I and type II serine-threonine kinase receptors, and transduce signals through the Smad signalling pathway. BMPs have been identified in mammalian ovaries, and functional studies have shown that they are involved in the regulation of oogenesis and folliculogenesis. This review summarizes the role of the BMP system during formation, growth and maturation of ovarian follicles in mammals.
    Zygote 01/2015; DOI:10.1017/S096719941400077X · 1.32 Impact Factor
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    • "RGMa may allow cells to respond to low levels of BMP ligands by changing the utilization of type-II receptors from BMPRII alone to both BMPRII and ActRIIA (Xia et al., 2007). In both human ovarian granulosa KGN cells "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGFβ) superfamily. BMPs mediate a highly conserved signal transduction cascade through the type-I and type-II serine/threonine kinase receptors and intracellular Smad proteins, which regulate multiple developmental and homeostatic processes. Mutations in this pathway can cause various diseases in humans, such as skeletal disorders, cardiovascular diseases, and various cancers. Multiple levels of regulation, including extracellular regulation, help to ensure proper spatiotemporal control of BMP signaling in the right cellular context. The family of repulsive guidance molecules (RGMs) and the type-I transmembrane protein neogenin, a paralog of DCC (Deleted in Colorectal Cancer), have been implicated in modulating the BMP pathway. In this review, we discuss the properties and functions of RGM proteins and neogenin, focusing on their roles in the modulation of BMP signal transduction. Mol. Reprod. Dev. © 2013 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 07/2013; DOI:10.1002/mrd.22199 · 2.68 Impact Factor
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    • "In mouse pulmonary artery smooth muscle cells, BMP-2/4 signaling requires BMPR-II, but not ActR-II or ActR-IIB. However, cells transfected with RGMa use both BMPR-II and ActR-II for BMP-2/4 signaling, suggesting that RGMa facilitates the use of ActR-II by BMP-2/4 (Xia et al., 2007). BMP-6 plays a key role in iron metabolism in hepatocytes. "
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    ABSTRACT: Activins are pluripotent hormones/growth factors that belong to the TGF-β superfamily of growth and differentiation factors (GDFs). They play a role in cell growth, differentiation and apoptosis, endocrine function, metabolism, wound repair, immune responses, homeostasis, mesoderm induction, bone growth, and many other biological processes. Activins and the related bone morphogenic proteins (BMPs) transduce their signal through two classes of single transmembrane receptors. The receptors possess intracellular serine/threonine kinase domains. Signaling occurs when the constitutively active type II kinase domain phosphorylates the type I receptor, which upon activation, phosphorylates intracellular signaling molecules. To generate antagonistic ligands, we generated chimeric molecules that disrupt the receptor interactions and thereby the phosphorylation events. The chimeras were designed based on available structural data to maintain high-affinity binding to type II receptors. The predicted type I receptor interaction region was replaced by residues present in inactive homologs or in related ligands with different type I receptor affinities.
    Vitamins & Hormones 01/2011; 85:105-28. DOI:10.1016/B978-0-12-385961-7.00006-8 · 1.78 Impact Factor
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