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Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

  1. Ryan S D'Souza
  2. Jun Y Lim
  3. Alper Turgut
  4. Kelly Servage
  5. Junmei Zhang
  6. Kim Orth
  7. Nisha Sosale
  8. Matthew Lazzara
  9. Jeremy Allegood
  10. James E Casanova  Is a corresponding author
  1. University of Virginia, United States
  2. University of Texas Southwestern Medical Center, United States
  3. HHMI/University of Texas Southwestern Medical Center, United States
  4. Virginia Commonwealth University, United States
Research Article
  • Cited 14
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Cite this article as: eLife 2020;9:e54113 doi: 10.7554/eLife.54113

Abstract

Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ryan S D'Souza

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
  2. Jun Y Lim

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
  3. Alper Turgut

    Cell Biology, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
  4. Kelly Servage

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7183-2865
  5. Junmei Zhang

    Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Kim Orth

    Department of Molecular Biology, HHMI/University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Kim Orth, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0678-7620
  7. Nisha Sosale

    Chemical Engineering, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
  8. Matthew Lazzara

    Chemical Engineering, University of Virginia, Charlottesville, United States
    Competing interests
    No competing interests declared.
  9. Jeremy Allegood

    Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, United States
    Competing interests
    No competing interests declared.
  10. James E Casanova

    Cell Biology, University of Virginia, Charlottesville, United States
    For correspondence
    jec9e@virginia.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0858-2899

Funding

National Institute of General Medical Sciences (RO1GM127361)

  • James E Casanova

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

Reviewing Editor

  1. Maddy Parsons, King's College London, United Kingdom

Publication history

  1. Received: December 2, 2019
  2. Accepted: March 30, 2020
  3. Accepted Manuscript published: April 1, 2020 (version 1)
  4. Version of Record published: April 15, 2020 (version 2)

Copyright

© 2020, D'Souza 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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