Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling

Abstract

Summary 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. The BMP pathway regulates 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 trans-membrane 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.

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

“…However, other work suggests that the interaction between matriptase-2 and RGMc is more complex, (e.g., independent of protease activity) [42]. Further work is needed to assess the requirement of RGMc cleavage by matriptase-2 in vivo and the precise link between matriptase-2, RGMc, BMP signaling, and hepcidin [10]. Nevertheless, these studies reveal important roles for proteolytic processing of RGMc in the regulation of hepcidin expression and iron levels.…”

“…This analysis also informed a potential molecular mechanism for JHH (see Glossary)-linked mutations in RGMc that occur at the binding interface with the BMP ligand, because these mutations disrupt the RGMc-BMP interaction. RGMc controls levels of hepcidin through BMP signaling and reduced hepcidin expression leads to the iron overload in the liver, heart, and pancreas observed in JHH [8][9][10].…”

“…This analysis also informed a potential molecular mechanism for JHH (see Glossary)-linked mutations in RGMc that occur at the binding interface with the BMP ligand, because these mutations disrupt the RGMc-BMP interaction. RGMc controls levels of hepcidin through BMP signaling and reduced hepcidin expression leads to the iron overload in the liver, heart, and pancreas observed in JHH [8][9][10].A comparison between the structures of the RGM-BMP and BMP-BMP type I receptor ectodomain complexes showed that RGM and the BMP type I receptor ectodomain of BMP-R1A share the same binding site on the BMP ligand. This was an unexpected discovery, because simultaneous binding of the BMP type I and type II receptors to the BMP ligand is an essential requirement for canonical, SMAD-dependent downstream signaling.…”

“…This processing serves to release RGMs from the cell surface in certain situations as well as to diversify the effects of the RGM signaling pathway and to control signaling duration following ligand binding. Here, we highlight some of the most recent insights into RGM processing and signaling in the context of specific biological functions, and refer readers to other reviews for a detailed discussion of other signaling mechanisms and biological effects [2,8,10,34,35]. …”

“…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].…”