Faculty Opinions recommendation of R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling.
Year: 2020
Type: peer-review
Abstract: R-spondins (RSPOs) amplify WNT signaling during development and regenerative responses.We previously demonstrated that RSPOs 2 and 3 potentiate WNT/b-catenin signaling in cells lacking leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4, 5 and 6 (Lebensohn and Rohatgi, 2018).We now show that heparan sulfate proteoglycans (HSPGs) act as alternative co-receptors for RSPO3 using a combination of ligand mutagenesis and ligand engineering.Mutations in RSPO3 residues predicted to contact HSPGs impair its signaling capacity.Conversely, the HSPG-binding domains of RSPO3 can be entirely replaced with an antibody that recognizes heparan sulfate (HS) chains attached to multiple HSPGs without diminishing WNTpotentiating activity in cultured cells and intestinal organoids.A genome-wide screen for mediators of RSPO3 signaling in cells lacking LGRs 4, 5 and 6 failed to reveal other receptors.We conclude that HSPGs are RSPO co-receptors that potentiate WNT signaling in the presence and absence of LGRs.
Author: John R Couchman
Institution: University of Copenhagen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American Heart Association, Alex's Lemonade Stand Foundation for Childhood Cancer, Cancer Research UK, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, KWF Kankerbestrijding, Oncode Institute, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, H2020 European Research Council
OpenAlex ID: W4245667110