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Cleavage activates Dispatched for Sonic Hedgehog ligand release

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 He...

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Autores principales: Stewart, Daniel P, Marada, Suresh, Bodeen, William J, Truong, Ashley, Sakurada, Sadie Miki, Pandit, Tanushree, Pruett-Miller, Shondra M, Ogden, Stacey K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811216/
https://www.ncbi.nlm.nih.gov/pubmed/29359685
http://dx.doi.org/10.7554/eLife.31678
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author Stewart, Daniel P
Marada, Suresh
Bodeen, William J
Truong, Ashley
Sakurada, Sadie Miki
Pandit, Tanushree
Pruett-Miller, Shondra M
Ogden, Stacey K
author_facet Stewart, Daniel P
Marada, Suresh
Bodeen, William J
Truong, Ashley
Sakurada, Sadie Miki
Pandit, Tanushree
Pruett-Miller, Shondra M
Ogden, Stacey K
author_sort Stewart, Daniel P
collection PubMed
description 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.
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spelling pubmed-58112162018-02-14 Cleavage activates Dispatched for Sonic Hedgehog ligand release Stewart, Daniel P Marada, Suresh Bodeen, William J Truong, Ashley Sakurada, Sadie Miki Pandit, Tanushree Pruett-Miller, Shondra M Ogden, Stacey K eLife Cell Biology 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. eLife Sciences Publications, Ltd 2018-01-23 /pmc/articles/PMC5811216/ /pubmed/29359685 http://dx.doi.org/10.7554/eLife.31678 Text en © 2018, Stewart et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Stewart, Daniel P
Marada, Suresh
Bodeen, William J
Truong, Ashley
Sakurada, Sadie Miki
Pandit, Tanushree
Pruett-Miller, Shondra M
Ogden, Stacey K
Cleavage activates Dispatched for Sonic Hedgehog ligand release
title Cleavage activates Dispatched for Sonic Hedgehog ligand release
title_full Cleavage activates Dispatched for Sonic Hedgehog ligand release
title_fullStr Cleavage activates Dispatched for Sonic Hedgehog ligand release
title_full_unstemmed Cleavage activates Dispatched for Sonic Hedgehog ligand release
title_short Cleavage activates Dispatched for Sonic Hedgehog ligand release
title_sort cleavage activates dispatched for sonic hedgehog ligand release
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811216/
https://www.ncbi.nlm.nih.gov/pubmed/29359685
http://dx.doi.org/10.7554/eLife.31678
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