Bridging the gap: heparan sulfate and Scube2 assemble Sonic hedgehog release complexes at the surface of producing cells

Decision making in cellular ensembles requires the dynamic release of signaling molecules from the producing cells into the extracellular compartment. One important example of molecules that require regulated release in order to signal over several cell diameters is the Hedgehog (Hh) family, because...

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Bibliographic Details
Published in:Scientific reports 2016-05, Vol.6 (1), p.26435-26435, Article 26435
Main Authors: Jakobs, P, Schulz, P, Ortmann, C, Schürmann, S, Exner, S, Rebollido-Rios, R, Dreier, R, Seidler, D G, Grobe, K
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Membrane - metabolism
Cell surface
Decision making
Hedgehog protein
Hedgehog Proteins - chemistry
Hedgehog Proteins - metabolism
HeLa Cells
Heparan sulfate
Heparan Sulfate Proteoglycans - metabolism
Humans
Membrane Proteins - metabolism
Mice
Protein Binding
Proteoglycans
Proteolysis
Signal Transduction
Sulfate
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Summary:Decision making in cellular ensembles requires the dynamic release of signaling molecules from the producing cells into the extracellular compartment. One important example of molecules that require regulated release in order to signal over several cell diameters is the Hedgehog (Hh) family, because all Hhs are synthesized as dual-lipidated proteins that firmly tether to the outer membrane leaflet of the cell that produces them. Factors for the release of the vertebrate Hh family member Sonic Hedgehog (Shh) include cell-surface sheddases that remove the lipidated terminal peptides, as well as the soluble glycoprotein Scube2 that cell-nonautonomously enhances this process. This raises the question of how soluble Scube2 is recruited to cell-bound Shh substrates to regulate their turnover. We hypothesized that heparan sulfate (HS) proteoglycans (HSPGs) on the producing cell surface may play this role. In this work, we confirm that HSPGs enrich Scube2 at the surface of Shh-producing cells and that Scube2-regulated proteolytic Shh processing and release depends on specific HS. This finding indicates that HSPGs act as cell-surface assembly and storage platforms for Shh substrates and for protein factors required for their release, making HSPGs critical decision makers for Scube2-dependent Shh signaling from the surface of producing cells.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep26435