Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate

J Cell Sci. 2022 Mar 15;135(6):jcs259297. doi: 10.1242/jcs.259297. Epub 2022 Mar 17.

Abstract

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-Golabi-Behmel 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. This article has an associated First Person interview with the first author of the paper.

Keywords: Glycosaminoglycans; Glypican; Hedgehog; Heparan sulfate; Signaling.

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Abnormalities, Multiple* / metabolism
  • Arrhythmias, Cardiac
  • Genetic Diseases, X-Linked
  • Gigantism
  • Glypicans* / genetics
  • Glypicans* / metabolism
  • Heart Defects, Congenital
  • Hedgehog Proteins* / genetics
  • Hedgehog Proteins* / metabolism
  • Heparan Sulfate Proteoglycans
  • Heparitin Sulfate*
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Signal Transduction

Substances

  • GPC3 protein, human
  • Glypicans
  • Hedgehog Proteins
  • Heparan Sulfate Proteoglycans
  • Heparitin Sulfate

Supplementary concepts

  • Simpson-Golabi-Behmel syndrome