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Babitt, J.L. et al. Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J. Biol. Chem. 280, 29820-29827

Harvard University, Cambridge, Massachusetts, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2005; 280(33):29820-7. DOI: 10.1074/jbc.M503511200
Source: PubMed

ABSTRACT

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor β (TGF-β) superfamily of ligands, which regulate
many mammalian physiologic and pathophysiologic processes. BMPs exert their effects through type I and type II serine/threonine
kinase receptors and the Smad intracellular signaling pathway. Recently, the glycosylphosphatidylinositol (GPI)-anchored protein
DRAGON was identified as a co-receptor for BMP signaling. Here, we investigate whether a homologue of DRAGON, repulsive guidance
molecule (RGMa), is similarly involved in the BMP signaling pathway. We show that RGMa enhances BMP, but not TGF-β, signals
in a ligand-dependent manner in cell culture. The soluble extracellular domain of RGMa fused to human Fc (RGMa.Fc) forms a
complex with BMP type I receptors and binds directly and selectively to radiolabeled BMP-2 and BMP-4. RGMa mediates BMP signaling
through the classical BMP signaling pathway involving Smad1, 5, and 8, and it up-regulates endogenous inhibitor of differentiation
(Id1) protein, an important downstream target of BMP signals. Finally, we demonstrate that BMP signaling occurs in neurons
that express RGMa in vivo. These data are consistent with a role for RGMa as a BMP co-receptor.

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    • "In contrast to the negative regulators, co-receptors for BMP ligands can enhance their signalling. Repulsive guidance molecules (RGMs, A, B and C) can enhance signalling of BMP2 and BMP4 as co-receptors606162. I-Smads suppress TGF-β signalling by either preventing R-Smad activation or competitively binding with Smad4 to block the formation of Smad hetero-complex[63,64]. "
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    ABSTRACT: Bone morphogenetic protein (BMP) belongs to transforming growth factor-β superfamily. To date, more than 20 BMPs have been identified in humans. BMPs play a critical role in embryonic and postnatal development, and also in maintaining homeostasis in different organs and tissues by regulating cell differentiation, proliferation, survival and motility. They play important roles in the development and progression of certain malignancies, including prostate cancer, breast cancer and lung cancer etc. Recently, more evidence shows that BMPs are also involved in tumour associated angiogenesis. For example BMP can either directly regulate the functions of vascular endothelial cells, or indirectly influence the angiogenesis via a regulation of angiogenic factors, such as vascular endothelial growth factor (VEGF). Such crosstalk can also be reflected in the interaction with other angiogenic factors, like hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF). All these factors are involved in the orchestration of the angiogenic process during tumour development and progression. Review of the relevant studies will provide a comprehensive prospective on current understanding and shed light on the corresponding therapeutic opportunity.
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    • "A breakthrough in understanding the mechanism of action of HJV in hepcidin regulation came when HJV was discovered to function as a co-receptor for the bone morphogenetic protein (BMP) signaling pathway (Babitt et al., 2006), analogous to its RGM family homologs (Babitt et al., 2005; Samad et al., 2005). Importantly, this BMP signaling function of HJV was demonstrated to be crucial for its role in regulating hepcidin expression (Babitt et al., 2006) (Figure 1). "
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    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.
    Full-text · Article · May 2014 · Frontiers in Pharmacology
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    • "Yet it is not known which, if any, of these RGMa-mediated processes is due to the potentiation of BMP signaling by RGMa. For example, BMP signaling occurs in neurons of the mouse adult spinal cord that expresses RGMa (Babitt et al., 2005), however it is not known if RGMa functions by mediating BMP signaling there. Many of the processes that RGMa is involved in require the function of the RGM receptor neogenin (discussed more later), but despite their overlapping expression patterns in some tissues, it is not known if both proteins function together via BMP signaling to regulate these processes in vivo. "
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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.
    Preview · Article · Jul 2013 · Molecular Reproduction and Development
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