title: Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells.
abstract: All morphogens of the Hedgehog (Hh) family are synthesized as dual-lipidated proteins, which results in their firm attachment to the surface of the cell in which they were produced. Thus, Hh release into the extracellular space requires accessory protein activities. We suggested previously that the proteolytic removal of N- and C-terminal lipidated peptides (shedding) could be one such activity. More recently, the secreted glycoprotein Scube2 (signal peptide, cubulin domain, epidermal-growth-factor-like protein 2) was also implicated in the release of Shh from the cell membrane. This activity strictly depended on the CUB domains of Scube2, which derive their name from the complement serine proteases and from bone morphogenetic protein-1/tolloid metalloproteinases (C1r/C1s, Uegf and Bmp1). CUB domains function as regulators of proteolytic activity in these proteins. This suggested that sheddases and Scube2 might cooperate in Shh release. Here, we confirm that sheddases and Scube2 act cooperatively to increase the pool of soluble bioactive Shh, and that Scube2-dependent morphogen release is unequivocally linked to the proteolytic processing of lipidated Shh termini, resulting in truncated soluble Shh. Thus, Scube2 proteins act as protease enhancers in this setting, revealing newly identified Scube2 functions in Hh signaling regulation.
authors: The Institute for Physiological Chemistry and Pathobiochemistry, Westfälische Wilhelms Universität Münster, Waldeyerstrasse 15, D-48149 Münster, Germany.
authors: Petra
authors: P
authors: Jakobs
authors: Sebastian
authors: S
authors: Exner
authors: Sabine
authors: S
authors: Schürmann
authors: Ute
authors: U
authors: Pickhinke
authors: Shyam
authors: S
authors: Bandari
authors: Corinna
authors: C
authors: Ortmann
authors: Sabine
authors: S
authors: Kupich
authors: Philipp
authors: P
authors: Schulz
authors: Uwe
authors: U
authors: Hansen
authors: Daniela G
authors: DG
authors: Seidler
authors: Kay
authors: K
authors: Grobe
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D006224:Cricetinae; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D059748:Proteolysis; D012995:Solubility
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D021382:Protein Sorting Signals; C469999:SCUBE2 protein, human; C509239:SHH protein, human; D000217:Acyltransferases; C105599:HHAT protein, human; D051722:ADAM Proteins
keywords: Hedgehog acyltransferase; Scube; Shedding; Sonic hedgehog