Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex
- University of Virginia, United States
- University of Texas Southwestern Medical Center, United States
- HHMI/University of Texas Southwestern Medical Center, United States
- Virginia Commonwealth University, United States
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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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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.
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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Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex
eLife 9:e54113.
https://doi.org/10.7554/eLife.54113
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