Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex
Ryan S D'Souza 1 , Jun Y Lim 1 , Alper Turgut 1 , Kelly Servage 2 3 , Junmei Zhang 1 , Kim Orth 2 3 , Nisha G Sosale 4 , Matthew J Lazzara 4 , Jeremy Allegood 5 , James E Casanova 1
PMID: 32234213 PMCID: PMC7159923 DOI: 10.7554/eLife.54113PMID: 32234213
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 (PM) 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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