Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
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...
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