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.

中文翻译：

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钙刺激的ORP3 / IQSec1复合物介导的粘着斑的分解

整联蛋白介导的粘着斑（FAs）的协调组装和拆卸对于细胞迁移至关重要。许多研究表明，FA的分解需要Ca ^2+的流入，但是我们对这一过程的理解仍然不完整。在这里，我们显示了通过STIM1 / Orai1钙通道（在FA附近聚集）流入的Ca ²⁺导致通过Ca ²⁺激活的GEF IQSec1激活GTPase Arf5，并且IQSec1和Arf5激活对于粘附拆卸至关重要。我们进一步证明，IQSec1与脂质转移蛋白ORP3形成复合物，并且Ca ²⁺大量涌入触发了该复合物向邻近FA的ER /质膜接触部位的PKC依赖性转运。除了变构激活IQSec1，ORP3还从PM中提取PI4P，以换取磷脂酰胆碱。ORP3介导的脂质交换对于FA转换也很重要。总之，这些发现确定了在细胞迁移过程中将钙流入与FA周转联系起来的新途径。