Glypicans shield the Wnt lipid moiety to enable signalling at a distance

McGough, Ian J.; Vecchia, Luca; Bishop, B.; Malinauskas, Tomas; Beckett, Karen; Joshi, Dhira; O’Reilly, Nicola; Siebold, Christian; Jones, E.Y.; Vincent, Jean‐Paul

doi:10.1038/s41586-020-2498-z

Cited by 102 publications

(91 citation statements)

References 52 publications

(11 reference statements)

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“…Glypicans regulate several morphogenetic gradients in addition to that of Hh (ie.Wnt, Bmp, FGF). It has also been described that Dlp class of glypicans shields the highly hydrophobic lipid moiety of Wnts from the aqueous environment helping to be handed over to Wnt receptors (McGough et al ., 2020). Dlp could hide the lipids while transferring Hh to its receptor Ptc.…”

Section: Discussionmentioning

confidence: 99%

Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

Simon

Jiménez-Jiménez

Seijo-Barandiarán

et al. 2020

Preprint

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The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication in development, tissue repair and cancer progression. These proteins can act as morphogens, inducing responses dependent on the ligand concentration in target cells located at a distance. Hh proteins are lipid modified and thereby have high affinity for membranes, which hinders the understanding of their spreading across tissues. Direct contact between cell membranes by filopodia-like structures (also known as cytonemes) could be the simplest explanation for Hh dispersal. To better understand this signaling mechanism, we have analyzed in Drosophila the interaction between the glypicans that, besides for other pathways, are necessary for Hh signaling, plus the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans (Dally and Dally-like protein) are required to maintain Ihog, but not Boi, protein levels. We also show that ectopic Ihog stabilizes cytonemes through its interaction with glypicans, and we determine that two Ihog fibronectin III domains are essential for this interaction. Our data suggest that this interaction with Ihog in cytonemes confers the specificity of glypicans for Hh signaling.

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Section: Discussionmentioning

confidence: 99%

Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

Simon

Jiménez-Jiménez

Seijo-Barandiarán

et al. 2020

Preprint

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“…However, Wntless does not migrate with the lipidated Wnt into the extracellular space [15]. The glypicans protect the lipid of Wnt proteins in the extracellular aqueous environment and act as a reservoir from which Wnt proteins can be passed to their receptors [16]. Structural studies have recently shown that these carrier proteins also utilize a palmitoleate binding pocket and provide further insight into this mechanism at a molecular level [16,17].…”

Section: Notum Deactivates Wnt Signalingmentioning

confidence: 99%

Small-Molecule Inhibitors of Carboxylesterase Notum

et al. 2021

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Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.

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“…Specifically, N-sulfo-rich glypicans form clusters that colocalize with Wnt8/Fzd/Lrp6 puncta in vivo in Xenopus embryos, acting as recruiting platforms that accumulate Wnt ligands and promote the assembly of Wnt signalosomes (Mii et al, 2017). Notably, glypicans of the Dlp (Dally-like protein) family have been recently shown to bind the Wnt palmitoleate through a hydrophobic tunnel in their core protein, shielding the lipid moiety from the aqueous environment and serving as reservoirs that hand Wnt proteins to signaling receptors (McGough et al, 2020). Furthermore, the presence of certain coreceptors may promote the enrichment of specific Wnt ligands within signalosomes, in a context-specific fashion.…”

Section: Initiating Wnt S I G Naling : a Ss Emb Ly Of The S I G Nalmentioning

confidence: 99%

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

Colozza

Koo

2021

Dev Growth Differ

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Wnt signaling is an evolutionarily conserved pathway involved in embryonic development and cell differentiation (Nusse & Clevers, 2017).In addition, it regulates many other processes, including cell growth and mitosis, adult stem cell homeostasis, and regeneration (Acebron & Niehrs, 2016;Nusse & Clevers, 2017;Reddien, 2018). Aberrant activation of the Wnt pathway lies at the basis of different types of malignancies, including colorectal, breast, and hepatic cancers.Historically, the first Wnt gene was identified in Drosophila melanogaster, following a screen for recessive mutant genes that affect segment patterning of fruit fly embryos. Because the mutant flies did not develop wings, the gene was named wingless (wg) (Sharma, 1973;Sharma & Chopra, 1976). Years later, the proto-oncogene integration site-1 (int-1) was discovered while studying mouse models of mammary carcinomas induced by DNA integrations of the mouse mammary tumor virus (MMTV) (Nusse & Varmus, 1982). Since Int-1 was found to be the mammalian orthologue of Wg, it was then renamed Wnt1 (Wingless + Int1) (Nusse et al., 1991).Wnts are secreted glycoproteins (Brown et al., 1987;Papkoff et al., 1987) that can activate divergent pathways, classically categorized as: (a) the canonical or β-catenin dependent pathway; and (b) the noncanonical branch, comprising the planar cell polarity and Ca 2+ pathways. Although some Wnts preferentially activate one or the other pathway, their specificity is less strict than previously thought and likely depends on the cell-specific context and the repertoire of receptors and components expressed, rather than on intrinsic properties. Indeed, while the serpentine Frizzled (Fzd) receptors are a shared component of all Wnt pathways, coreceptors such as the low-density lipoprotein receptor-related protein 5 and 6 (Lrp5/6;

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Glypicans shield the Wnt lipid moiety to enable signalling at a distance

Cited by 102 publications

References 52 publications

Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

Glypicans specifically regulate Hedgehog signaling through their interaction with Ihog in cytonemes

Small-Molecule Inhibitors of Carboxylesterase Notum

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

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