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bioRxiv · 10.1101/866392

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

Casanova, J. E.·D'Souza, R. S.·Lim, J. Y.·Servage, K.·Zhang, J.·Orth, K.·Sosale, N.·Lazzara, M.·Allegood, J.
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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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Casanova, J. E., D'Souza, R. S., Lim, J. Y., Servage, K., Zhang, J., Orth, K., Sosale, N., Lazzara, M., Allegood, J.. 2019-12-05. Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex. https://doi.org/10.1101/866392

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