title: Bridging the gap: heparan sulfate and Scube2 assemble Sonic hedgehog release complexes at the surface of producing cells.
abstract: 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.
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Jakobs
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schulz
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Ortmann
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schürmann
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Exner
authors.affiliation: Center for Medical Biotechnology#, University of Duisburg-Essen, 45117 Essen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Rebollido-Rios
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Dreier
authors.affiliation: Centre for Internal Medicine, Hannover Medical School I3, EB2/R3110, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: D G
authors.initials: DG
authors.lastname: Seidler
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Waldeyerstr. 15, D-48149 Münster, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Grobe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006367:HeLa Cells; D053823:Hedgehog Proteins / Q000737:chemistry / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; C469999:SCUBE2 protein, human; C509239:SHH protein, human