Department of Molecular Biology, University of Texas Southwest Medical Center, Dallas, United States; Howard Hughes Medical Institute, Dallas, United States
Junmei Zhang
Department of Cell Biology, University of Virginia Health System, Charlottesville, United States
Department of Molecular Biology, University of Texas Southwest Medical Center, Dallas, United States; Howard Hughes Medical Institute, Dallas, United States
Nisha G Sosale
Department of Chemical Engineering, University of Virginia, Charlottesville, United States
Matthew J Lazzara
Department of Chemical Engineering, University of Virginia, Charlottesville, United States
Jeremy Allegood
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, United States
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.
