Molecular biology, genetics and biochemistry of the repulsive guidance molecule family

Severyn, Christopher J.; Shinde, Ujwal; Rotwein, Peter

doi:10.1042/bj20090978

Cited by 56 publications

(60 citation statements)

References 86 publications

(214 reference statements)

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“…RGMc have been implicated in BMP signaling (Corradini et al, 2009;Severyn et al, 2009). We have previously shown that the C. elegans RGM protein DRAG-1 is a positive modulator of Sma/Mab signaling (Tian et al, 2010).…”

Section: Research Article Development 140 (19)mentioning

confidence: 99%

The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans

et al. 2013

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The deleted in colorectal cancer (DCC) homolog neogenin functions in both netrin- and repulsive guidance molecule (RGM)-mediated axon guidance and in bone morphogenetic protein (BMP) signaling. How neogenin functions in mediating BMP signaling is not well understood. We show that the sole C. elegans DCC/neogenin homolog UNC-40 positively modulates a BMP-like pathway by functioning in the signal-receiving cells at the ligand/receptor level. This function of UNC-40 is independent of its role in netrin-mediated axon guidance, but requires its association with the RGM protein DRAG-1. We have identified the key residues in the extracellular domain of UNC-40 that are crucial for UNC-40-DRAG-1 interaction and UNC-40 function. Surprisingly, the extracellular domain of UNC-40 is sufficient to promote BMP signaling, in clear contrast to the requirement of its intracellular domain in mediating axon guidance. Mouse neogenin lacking the intracellular domain is also capable of mediating BMP signaling. These findings reveal an unexpected mode of action for neogenin regulation of BMP signaling.

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Section: Research Article Development 140 (19)mentioning

confidence: 99%

The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans

et al. 2013

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“…In particular, a family of repulsive guidance molecules (RGMs) has recently been found to bind different BMPs with high affinity and act as BMP coreceptors in tissue culture experiments Babitt et al, 2005;Babitt et al, 2006). RGM family proteins are GPI (glycosylphosphatidylinositol)-linked membrane-associated proteins Severyn et al, 2009). Vertebrates have four RGMs: RGMa, RGMb (DRAGON), RGMc (hemojuvelin or HJV) and RGMd (Camus and Lambert, 2007).…”

Section: Introductionmentioning

confidence: 99%

The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway inCaenorhabditis elegans

et al. 2010

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SUMMARYThe bone morphogenetic protein (BMP) signaling pathway regulates multiple developmental and homeostatic processes. Mutations in the pathway can cause a variety of somatic and hereditary disorders in humans. Multiple levels of regulation, including extracellular regulation, ensure proper spatiotemporal control of BMP signaling in the right cellular context. We have identified a modulator of the BMP-like Sma/Mab pathway in C. elegans called DRAG-1. DRAG-1 is the sole member of the repulsive guidance molecule (RGM) family of proteins in C. elegans, and is crucial in regulating body size and mesoderm development. Using a combination of molecular genetic and biochemical analyses, we demonstrate that DRAG-1 is a membraneassociated protein that functions at the ligand-receptor level to modulate the Sma/Mab pathway in a cell-type-specific manner. We further show that DRAG-1 positively modulates this BMP-like pathway by using a novel Sma/Mab-responsive reporter. Our work provides a direct link between RGM proteins and BMP signaling in vivo and a simple and genetically tractable system for mechanistic studies of RGM protein regulation of BMP pathways.

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“…Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. 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].…”

mentioning

confidence: 99%

“…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]. …”

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confidence: 99%

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

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Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho) biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. RGMs: A Small Gene Family with Widespread EffectsGuidance molecules, initially observed to direct growing axons during embryogenesis [1], also have crucial roles in the morphogenesis and homeostasis of non-neuronal tissues by controlling a plethora of cellular processes, ranging from cell division and migration to differentiation and death. Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. 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 [5-10] 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].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin. In this review, we discuss recent highlights in RGM research, from novel structural data to previously unexplored signaling mechanisms and cellular functions. Structural Insight into Ligand-Receptor InteractionsFor many years, RGMs posed a molecular puzzle because of a general lack of structural homologies to any known protein fold. Recent studies have shed light on their 3D structure and identified two ordered and disulfide-stabiliz...

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Molecular biology, genetics and biochemistry of the repulsive guidance molecule family

Cited by 56 publications

References 86 publications

The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans

The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans

The RGM protein DRAG-1 positively regulates a BMP-like signaling pathway inCaenorhabditis elegans

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

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