Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) 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-beta, 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.
Program in Membrane Biology and Division of Nephrology, Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
Jodie L
JL
Babitt
Ying
Y
Zhang
Tarek A
TA
Samad
Yin
Y
Xia
Jie
J
Tang
Jason A
JA
Campagna
Alan L
AL
Schneyer
Clifford J
CJ
Woolf
Herbert Y
HY
Lin
D000595:Amino Acid Sequence; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D058851:GPI-Linked Proteins; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D051381:Rats; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D013116:Spinal Cord / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017978:Receptors, Growth Factor; C483496:Rgma protein, mouse; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C497400:Smad1 protein, rat; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; C497799:Smad5 protein, rat; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D052004:Bone Morphogenetic Protein Receptors