17Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. 18 Many studies have shown that FA disassembly requires Ca 2+ influx, however our understanding of this process 19 remains incomplete. Here we show that Ca 2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, 20 leads to activation of the GTPase Arf5 via the Ca 2+ -activated GEF IQSec1, and that both IQSec1 and Arf5 21 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid 22 transfer protein ORP3, and that Ca 2+ influx triggers PKC-dependent translocation of this complex to ER/plasma 23 membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P 24 from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA 25 turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell 26 migration. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 100 activation of Arf5 and insertion of PC into the plasma membrane are both important to promote adhesion 101disassembly. Taken together, our findings establish a spatial and mechanistic link between calcium influx at 102 ER/PM contact sites and focal adhesion turnover mediated by ORP3 and IQSec1-activated Arf5.
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