Cleavage activates dispatched for Sonic Hedgehog ligand release

Area of Science:

• Molecular Biology
• Developmental Biology
• Cell Signaling

Background:

• The Hedgehog (Hh) signaling pathway is crucial for tissue morphogenesis during development.
• Dysregulation of Hh signaling is implicated in developmental disorders and cancer.
• Dispatched (DISP) is a transmembrane protein essential for Hh ligand deployment but its regulation is poorly understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling Dispatched protein activity.
• To investigate the role of post-translational modifications in Dispatched function.
• To understand how Dispatched maturation impacts Hedgehog pathway signaling.

Main Methods:

• Investigated vertebrate Dispatched protein processing using biochemical assays.
• Utilized cell-surface localization studies in polarized epithelial cells.
• Employed site-directed mutagenesis to analyze the effect of cleavage site mutations on Dispatched trafficking and Hh signaling in vivo.

Main Results:

• Identified proprotein convertase-mediated cleavage at a conserved site in the first extracellular loop as the activation mechanism for vertebrate Dispatched.
• Demonstrated that Dispatched processing occurs at the cell surface, directing its membrane re-localization in polarized epithelial cells.
• Showed that mutations in the Dispatched cleavage site impair membrane trafficking and reduce Hh ligand release, compromising pathway activity.

Conclusions:

• Proprotein convertase-mediated cleavage is a critical step for Dispatched maturation and functional competency.
• This cleavage event is required for proper Dispatched membrane localization and efficient Hedgehog ligand deployment.
• Understanding Dispatched regulation via cleavage provides insights into controlling Hedgehog signaling in development and disease contexts.