Journal article
R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling
- Abstract:
- R-spondins (RSPOs) amplify WNT signaling during development and regenerative responses. We previously demonstrated that RSPOs 2 and 3 potentiate WNT/β-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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 2.8MB, Terms of use)
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- Publisher copy:
- 10.7554/elife.54469
Authors
- Publisher:
- eLife Sciences Publications
- Journal:
- eLife More from this journal
- Volume:
- 9
- Publication date:
- 2020-05-20
- Acceptance date:
- 2020-04-25
- DOI:
- EISSN:
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2050-084X
- Pmid:
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32432544
- Language:
-
English
- Keywords:
- Pubs id:
-
1106679
- Local pid:
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pubs:1106679
- Deposit date:
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2020-06-12
Terms of use
- Copyright holder:
- free of all copyright
- Copyright date:
- 2020
- Rights statement:
- This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
- Licence:
- CC Public Domain Dedication (CC0)
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