期刊
ELIFE
卷 9, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.54469
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资金
- National Institutes of Health [GM118082, AI141970]
- American Heart Association [14POST20370057]
- Alex's Lemonade Stand Foundation for Childhood Cancer
- National Institutes of Health
- Cancer Research UK [C20724/A14414, C20724/A26752]
- European Research Council [647278]
- Burroughs Wellcome Fund
- Dutch Cancer Society Oncode Institute
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek [91815604, 91218050]
- Stanford Dean's Fund
- NATIONAL CANCER INSTITUTE [ZIABC010891, ZIABC011901] Funding Source: NIH RePORTER
- European Research Council (ERC) [647278] Funding Source: European Research Council (ERC)
R-spondins (RSPOs) amplify WNT signaling during development and regenerative responses. We previously demonstrated that RSPOs 2 and 3 potentiate WNT/beta-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 WNT-potentiating 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.
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