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


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.

16 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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; -1:1-17. DOI:10.1017/S096719941400077X · 1.42 Impact Factor
  • Source
    • "All RGMs share the ability to bind to the BMP2/BMP4 subfamily and enhance BMP2/BMP4 signaling (Babitt et al., 2005, 2006; Samad et al., 2005; Wu et al., 2012). Moreover, all RGMs utilize BMP type I receptors ALK2, ALK3, and ALK6, and allow preferential signaling through the BMP type II receptor ACTRIIA (Xia et al., 2007, 2008, 2010). However, HJV is unique from other RGMs in that it exhibits preferential ability to bind to the BMP5/BMP6/BMP7 subfamily compared with RGMA and RGMB (Wu et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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; 80(9). DOI:10.1002/mrd.22199 · 2.53 Impact Factor
Show more