RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Abstract

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...

Exploring specific prognostic biomarkers in triple-negative breast cancer

“…Recently, a large body of literature have shown that FOXC1 plays a critical role in proliferation, metastasis, survival and chemosensitivity of TNBC, served as a potential therapeutic target [51][52][53] . Likewise, RGMA initially has been considered as an axon guidance molecule during embryogenesis 54 , but lately as a potential tumor suppressor in some cancers [55][56][57] . However, less is known about the explicit function of RGMA in TNBC.…”

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“…Many of these CAMs activate intracellular signaling cascades that converge on common pathways to impact cytoskeletal function and neurite outgrowth (see Figures 2, 3). Many of these CAMs are extensively reviewed (Herron et al, 2009;Siebold et al, 2017;Sytnyk et al, 2017;Chooi and Chew, 2019), thus this section will highlight some of the key players and mechanisms that underlie glial cell-neuron interactions.…”

“…For example, several of the previously discussed molecules above including RGMa, NG2, and many of the plexins (semaphorin receptors) signal through the RhoA/ROCK pathway to inhibit axon growth and guidance. RGMa is part of the larger family of GPI-linked repulsive guidance molecules (RGMs) that signals through interactions with the type 1 transmembrane protein neogenin (reviewed in De Vries and Cooper, 2008;Siebold et al, 2017). RGMa can act in trans to promote the formation of neogenin receptor dimers, which initiates FIGURE 3 | Molecular mechanisms underlying glial-axon growth cone repulsive signals.…”

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“…A critical molecular mechanism responsible for the recruitment of Arp2/3 and the WRC to cadherins has recently been discovered. Neogenin, a multi-functional receptor for Netrin and the Repulsive Guidance Molecules (Rajagopalan et al, 2004;De Vries and Cooper, 2008;Kee et al, 2008;O'Leary et al, 2015;Siebold et al, 2017), has been identified as a pivotal component of the branched actin nucleation machinery governing junctional stability and tension (Lee et al, 2016;O'Leary et al, 2017). The WRC interacting receptor sequence (WIRS), found in the intracellular domain of Neogenin, binds to a highly conserved binding pocket within the WRC composed of the Cyfip1 and Abi subunits (Figure 2) (Chen et al, 2014;Lee et al, 2016).…”