Cleavage activates Dispatched for Sonic Hedgehog ligand release

Author:

Stewart Daniel P1,Marada Suresh1,Bodeen William J12ORCID,Truong Ashley1,Sakurada Sadie Miki13,Pandit Tanushree1,Pruett-Miller Shondra M13,Ogden Stacey K1ORCID

Affiliation:

1. Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, United States

2. Integrated Program in Biomedical Sciences, University of Tennessee Health Sciences Center, Memphis, United States

3. Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, United States

Abstract

Hedgehog ligands activate an evolutionarily conserved signaling pathway that provides instructional cues during tissue morphogenesis, and when corrupted, contributes to developmental disorders and cancer. The transmembrane protein Dispatched is an essential component of the machinery that deploys Hedgehog family ligands from producing cells, and is absolutely required for signaling to long-range targets. Despite this crucial role, regulatory mechanisms controlling Dispatched activity remain largely undefined. Herein, we reveal vertebrate Dispatched is activated by proprotein convertase-mediated cleavage at a conserved processing site in its first extracellular loop. Dispatched processing occurs at the cell surface to instruct its membrane re-localization in polarized epithelial cells. Cleavage site mutation alters Dispatched membrane trafficking and reduces ligand release, leading to compromised pathway activity in vivo. As such, convertase-mediated cleavage is required for Dispatched maturation and functional competency in Hedgehog ligand-producing cells.

Funder

National Institute of General Medical Sciences

St. Jude Children's Research Hospital

National Cancer Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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