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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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Ca2+ coordination controls sonic hedgehog structure and its Scube2-regulated release
Petra Jakobs1, Philipp Schulz1, Sabine Schürmann1
1Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, D-48149 Münster, Germany.
Journal of Cell Science
|August 6, 2017
Summary
Scube2 enhances Sonic hedgehog (Shh) shedding and activation by cleaving inhibitory N-terminal peptides. This process, regulated by calcium and Scube2 domains, explains Shh patterning activity differences between vertebrates and invertebrates.
Area of Science:
- Cellular biology
- Molecular signaling
- Developmental biology
Background:
- Proteolytic shedding of cell-surface ligands regulates cell-cell communication.
- Sonic hedgehog (Shh) is a dual-lipidated protein crucial for development, requiring processing for activation.
- Scube2 (signal sequence, cubulin (CUB) domain, epidermal growth factor (EGF)-like protein 2) enhances Shh release and activation, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which Scube2 regulates the proteolytic processing and activation of Sonic hedgehog (Shh).
- To investigate the roles of Scube2 domains and calcium in Shh shedding.
- To explain the differential patterning activity of Shh in vertebrates versus invertebrates.
Main Methods:
- Biochemical assays to analyze Shh processing.
- Domain-specific analysis of Scube2 function.
- Calcium dependency studies.
Main Results:
- Scube2 EGF domains mediate specific proteolysis of the inhibitory Shh N-terminus.
- Scube2 CUB domains complete processing by reversing steric masking of the N-terminal peptide.
- Steric masking is regulated by calcium (Ca2+) occupancy of Shh ectodomains.
- Scube2 uncouples Shh peptide processing from lipid-mediated positioning.
Conclusions:
- Scube2 employs a novel mechanism involving its EGF and CUB domains to regulate Shh shedding and activation.
- Calcium-dependent steric masking at the substrate level represents a new regulatory mode for proteolytic shedding.
- Scube2's function explains why N-terminally unlipidated Shh exhibits patterning activity in vertebrates but not in invertebrates lacking Scube orthologs.
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