Cleavage activates Dispatched for Sonic Hedgehog ligand release

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.

Article and author information

Author details

  1. Daniel P Stewart

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Suresh Marada

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. William J Bodeen

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0557-4826
  4. Ashley Truong

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sadie Miki Sakurada

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tanushree Pandit

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Shondra M Pruett-Miller

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Stacey K Ogden

    Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States
    For correspondence
    stacey.ogden@stjude.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8991-3065

Funding

National Institute of General Medical Sciences (R01GM114049)

  • Stacey K Ogden

St. Jude Children's Research Hospital

  • Stacey K Ogden

National Cancer Institute (P30CA021765)

  • Stacey K Ogden

National Institute of General Medical Sciences (R35GM122546)

  • Stacey K Ogden

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Roel Nusse, Stanford University, United States

Publication history

  1. Received: August 31, 2017
  2. Accepted: January 22, 2018
  3. Accepted Manuscript published: January 23, 2018 (version 1)
  4. Version of Record published: February 13, 2018 (version 2)
  5. Version of Record updated: February 14, 2018 (version 3)

Copyright

© 2018, Stewart et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Daniel P Stewart
  2. Suresh Marada
  3. William J Bodeen
  4. Ashley Truong
  5. Sadie Miki Sakurada
  6. Tanushree Pandit
  7. Shondra M Pruett-Miller
  8. Stacey K Ogden
(2018)
Cleavage activates Dispatched for Sonic Hedgehog ligand release
eLife 7:e31678.
https://doi.org/10.7554/eLife.31678

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