{"doi":"10.7554/elife.54469","title":"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.","journal":"eLife","year":2020,"id":59394,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":67,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":312314,"name":"Peter van Kerkhof","orcid":"0000-0002-8954-2230","position":1,"is_corresponding":false},{"id":312315,"name":"Ingrid Jordens","orcid":"0000-0001-7865-2816","position":2,"is_corresponding":false},{"id":81237,"name":"Tomas Malinauskas","orcid":"0000-0002-4847-5529","position":3,"is_corresponding":false},{"id":312316,"name":"Ganesh V. Pusapati","orcid":"0000-0002-1406-2566","position":4,"is_corresponding":false},{"id":312317,"name":"Joseph K. McKenna","orcid":"0000-0002-3921-4933","position":5,"is_corresponding":false},{"id":255114,"name":"Dan Li","orcid":"0000-0002-9783-5340","position":6,"is_corresponding":false},{"id":227957,"name":"Jan E. Carette","orcid":"0000-0002-5187-8070","position":7,"is_corresponding":false},{"id":255131,"name":"Mitchell Ho","orcid":"0000-0002-9152-5405","position":8,"is_corresponding":false},{"id":312318,"name":"Christian Siebold","orcid":"0000-0002-6635-3621","position":9,"is_corresponding":false},{"id":312319,"name":"Madelon M. Maurice","orcid":"0000-0001-6885-5361","position":10,"is_corresponding":false},{"id":312320,"name":"Andres M. Lebensohn","orcid":"0000-0002-4224-8819","position":11,"is_corresponding":false},{"id":312321,"name":"Rajat Rohatgi","orcid":"0000-0001-7609-8858","position":12,"is_corresponding":false},{"id":312313,"name":"Ramin Dubey","orcid":"0000-0002-0687-5831","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T21:07:59.189921Z","pmid":"32432544","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}