{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:32:14Z","timestamp":1790757134313,"version":"4.1.0"},"reference-count":97,"publisher":"The Company of Biologists","issue":"6","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 GM122920"],"award-info":[{"award-number":["R01 GM122920"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F31GM120833"],"award-info":[{"award-number":["F31GM120833"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32GM007226"],"award-info":[{"award-number":["T32GM007226"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["GM135262"],"award-info":[{"award-number":["GM135262"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000191","name":"Kidney Foundation of Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000191","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson\u2013Golabi\u2013Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.259297","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T10:16:12Z","timestamp":1644488172000},"source":"Crossref","is-referenced-by-count":21,"title":["Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate"],"prefix":"10.1242","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-6915","authenticated-orcid":false,"given":"Yulu Cherry","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Biology, Hood College, Frederick, MD 21701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1967-5919","authenticated-orcid":false,"given":"Bradley M.","family":"Wierbowski","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0748-9545","authenticated-orcid":false,"given":"Adrian","family":"Salic","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"2022031714034371900_JCS259297C1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/ng1095-137","article-title":"Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1)","volume":"11","author":"Ahn","year":"1995","journal-title":"Nat. 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Perspect. 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