Neogenin recruitment of the WAVE regulatory complex maintains adherens junction stability and tension

Lee, Natalie K.; Fok, Ka Wai; White, Amanda; Wilson, Nicole H.; O′Leary, Conor; Cox, Hayley L.; Michael, Magdalene; Yap, Alpha S.; Cooper, Helen

doi:10.1038/ncomms11082

Cited by 37 publications

(61 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neogenin also affects E-cadherin recycling, but whether this effect depends on its ability to control actin dynamics is unknown. Knockdown of RGMa induces defects in AJ stability and WRC localization similar to those observed following Neogenin depletion [62]. This suggests that RGMa and Neogenin act together at the AJ.…”

Section: Actin Regulation During Epithelial Cell Adhesionsupporting

confidence: 52%

“…The actin ring undergoes continuous turnover and failure to rebuild the ring causes loss of adhesion. Interestingly, recent work identified Neogenin as a key component of the actin nucleation machinery governing AJ stability [62]. Neogenin promotes the formation of stable actin rings at AJs by spatially coupling Arp2/3-mediated actin nucleation to the AJ via recruitment of the wave regulatory complex (WRC) (Figure 2).…”

Section: Actin Regulation During Epithelial Cell Adhesionmentioning

confidence: 99%

See 1 more Smart Citation

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

View full text Add to dashboard Cite

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...

show abstract

Section: Actin Regulation During Epithelial Cell Adhesionsupporting

confidence: 52%

Section: Actin Regulation During Epithelial Cell Adhesionmentioning

confidence: 99%

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

View full text Add to dashboard Cite

show abstract

“…3B). Neogenin also recruits the WAVE regulatory complex (WRC) and activates the actin related protein 2/3 complex (Arp2/3) (Lee et al 2016). The WRC comprises five subunits organized into the Sra/Nap and WAVE/Abi/HSPC300 subcomplexes Verma et al 2012).…”

Section: Netrins and Adherens Junctionsmentioning

confidence: 99%

“…The WRC comprises five subunits organized into the Sra/Nap and WAVE/Abi/HSPC300 subcomplexes Verma et al 2012). Neogenin directly interacts with, and recruits, the WRC to AJs via a WRC interacting receptor sequence (WIRS) present in its cytoplasmic domain (Lee et al 2016). This interaction requires Rac activation downstream from RGMa-mediated engagement of neogenin and leads to Arp2/3 activation at AJs that modulates tension through peri-junctional nucleation of F-actin (Lee et al 2016).…”

Section: Netrins and Adherens Junctionsmentioning

confidence: 99%

“…Neogenin directly interacts with, and recruits, the WRC to AJs via a WRC interacting receptor sequence (WIRS) present in its cytoplasmic domain (Lee et al 2016). This interaction requires Rac activation downstream from RGMa-mediated engagement of neogenin and leads to Arp2/3 activation at AJs that modulates tension through peri-junctional nucleation of F-actin (Lee et al 2016). These findings identify neogenin as a critical factor that regulates the maintenance, integrity, and stability of AJs.…”

Section: Netrins and Adherens Junctionsmentioning

confidence: 99%

See 1 more Smart Citation

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

Beamish

Hinck

Kennedy

2017

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

The field of axon guidance was revolutionized over the past three decades by the identification of highly conserved families of guidance cues and receptors. These proteins are essential for normal neural development and function, directing cell and axon migration, neuron-glial interactions, and synapse formation and plasticity. Many of these genes are also expressed outside the nervous system in which they influence cell migration, adhesion and proliferation. Because the nervous system develops from neural epithelium, it is perhaps not surprising that these guidance cues have significant nonneural roles in governing the specialized junctional connections between cells in polarized epithelia. The following review addresses roles for ephrins, semaphorins, netrins, slits and their receptors in regulating adherens, tight, and gap junctions in nonneural epithelia and endothelia.

show abstract

The regulation of junctional actin dynamics by cell adhesion receptors

Steinbacher

Ebnet

2018

Histochem Cell Biol

View full text Add to dashboard Cite

The formation of cell-cell junctions and the development of stable cell-cell adhesion require the association of actin filaments with the sites of cell-cell adhesion. From the initial formation of cell-cell junctions, which appear as punctate, spot-like junctions, to the formation of a stable actin belt that runs adjacent to cell-cell junctions, the actin cytoskeleton is closely associated with the adhesion apparatus. Importantly, the junctional actin is highly dynamic, even after the maturation of intercellular junctions and the development of apico-basal polarity. Regulators of both branched actin networks and of linear actin cables have been identified at cell-cell junctions, in particular at adherens junctions but also at tight junctions. These regulators of actin dynamics are often directly or indirectly associated with cell adhesion receptors, suggesting a critical role for cell adhesion molecules for the recruitment of regulators of actin dynamics to cell-cell junctions. Here, we review the recent developments on the role of cell adhesion molecules at epithelial and endothelial cell-cell junctions in the regulation of junctional actin dynamics.

show abstract

Neogenin recruitment of the WAVE regulatory complex maintains adherens junction stability and tension

Cited by 37 publications

References 61 publications

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

The regulation of junctional actin dynamics by cell adhesion receptors

Contact Info

Product

Resources

About