DRAGON, a Bone Morphogenetic Protein Co-receptor

Abstract

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)␤ superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGF␤ ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGF␤ signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGF␤ ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling. Transforming growth factor beta (TGF␤)1 superfamily ligands that include the TGF␤, bone morphogenetic protein (BMP), growth and differentiation factor, and nodal-related families play a pleiotropic role in vertebrate development by influencing cell specification, differentiation, proliferation, patterning, and migration (1, 2). These functions require the tight control of ligand production, ensuring a highly ordered spatiotemporal distribution and specific activation, via receptor complexes, of particular intracellular signaling pathways. The TGF␤/activin/nodal ligand subfamily contributes to the specification of endoderm and mesoderm in pregastrula embryos and at gastrula stages, to dorsal mesoderm formation and anterior-posterior patterning (3, 4). Later, TGF␤ ligands influence the body axis and patterning of the nervous system (5). BMPs, a second major ligand subfamily, contribute to the ventralization of germ layers in the early embryo and suppress the default neural cell fate of the ectoderm (6). BMPs also participate later in development in the formation and patterning of the neural crest, heart, blood, kidney, limb, muscle, and skeletal system (7).Signal transduction in the BMP subfamily is initiated by ligand binding to a receptor complex composed of two type I and two type II receptors. Three different BMP type I receptors (activin receptor-like kinase ALK2, ALK3, and ALK6) and three BMP type II receptors (BMP type II receptor (BMPRII), activin type IIA receptor (ActRIIA), activin type IIB receptor (ActRIIB)), each with intracellular serine/threonine kinase domains, have been identified (8). Ligand binding induces phosphorylation of the type I receptor by the type II receptor, which leads to phosphorylation of cytoplasmic receptor-activated Smads. The BMP subfamily signals through one set...

Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin

“…Recent studies have demonstrated that RGMa, RGMb, and RGMc are able to bind BMP-2, -4, and -9 and have suggested that each RGM may function as a BMP coreceptor (2,4,36,46). We performed a series of in vitro binding experiments with RGMc and recombinant BMP-2 to determine whether these two proteins interacted directly with each other.…”

“…BMPs are soluble proteins that bind to specific cell-surface receptors, which function as ligand-stimulated serine-threonine protein kinases, and activate several intracellular mediators, including members of the Smad family of transcriptional activators (39,43). Several reports have concluded that all three RGM proteins when expressed on the cell membrane can function as putative BMP coreceptors and can enhance BMP-stimulated activation of promoter-reporter genes (2,4,36,46). Cellassociated RGMc has been found to increase BMP-2-mediated induction of hepcidin promoter activity and hepcidin gene expression (2,3), while soluble RGMc in contrast appears to inhibit hepcidin mRNA accumulation (3,19,21).…”

“…Recent studies have indicated that RGMs may modulate the actions of bone morphogenetic proteins (BMPs) 2, 4, and 9 (2,4,36,42). BMPs comprise a subset of the transforming growth factor (TGF)-␤ superfamily of growth factors and are involved in a wide range of developmental processes (39,43).…”

The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system

“…Both RGMs signal via BMP receptors, ALK3, ALK6 and Smad 1; no clear differences in the interaction of the RGM family members with the BMPs have been detected by the authors and both RGMs have been reported to enhance BMP signalling (Babitt et al 2005;Samad et al 2005). The role of BMP proteins in retinotectal map formation is currently not clear.…”

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

“…RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5][6][7][8][9][10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].…”