R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
eLife Sciences Publications
2020
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| _version_ | 1826289973682241536 |
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| author | Dubey, R van Kerkhof, P Jordens, I Malinauskas, T Pusapati, GV McKenna, JK Li, D Carette, JE Ho, M Siebold, C Maurice, M Lebensohn, AM Rohatgi, R |
| author_facet | Dubey, R van Kerkhof, P Jordens, I Malinauskas, T Pusapati, GV McKenna, JK Li, D Carette, JE Ho, M Siebold, C Maurice, M Lebensohn, AM Rohatgi, R |
| author_sort | Dubey, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:37:04Z |
| format | Journal article |
| id | oxford-uuid:a9269def-3679-4faf-a9d6-12cca0ba03c7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:37:04Z |
| publishDate | 2020 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:a9269def-3679-4faf-a9d6-12cca0ba03c72022-03-27T03:06:32ZR-spondins engage heparan sulfate proteoglycans to potentiate WNT signalingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a9269def-3679-4faf-a9d6-12cca0ba03c7EnglishSymplectic ElementseLife Sciences Publications2020Dubey, Rvan Kerkhof, PJordens, IMalinauskas, TPusapati, GVMcKenna, JKLi, DCarette, JEHo, MSiebold, CMaurice, MLebensohn, AMRohatgi, RR-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. |
| spellingShingle | Dubey, R van Kerkhof, P Jordens, I Malinauskas, T Pusapati, GV McKenna, JK Li, D Carette, JE Ho, M Siebold, C Maurice, M Lebensohn, AM Rohatgi, R R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title | R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title_full | R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title_fullStr | R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title_full_unstemmed | R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title_short | R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling |
| title_sort | r spondins engage heparan sulfate proteoglycans to potentiate wnt signaling |
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