FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly
FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly
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DOI：
10.1038/ncb3333
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发表时间：
2016-05-01
影响因子：
21.3
通讯作者：
Gundersen, Gregg G.
中科院分区：
文献类型：
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作者：
Nader, Guilherme P. F.;Ezratty, Ellen J.;Gundersen, Gregg G.
整合素内吞循环对细胞迁移至关重要，但回收的整合素如何组装成新的粘附尚不清楚。通过同步内吞解体的焦点粘连（FA），我们发现，回收整合素重新组装FA符合他们返回到细胞表面，并依赖于Rab5和Rab11。出乎意料的是，内吞整合素在内体中保持活性但未配体化的状态。FAK和Src激酶与内吞整合素共定位，分别通过调节整合素活化和再循环对FA重组至关重要。FAK通过以I型磷脂酰肌醇磷酸激酶（PIPKI γ）依赖性方式维持Talin与Rab11内体的结合来维持活性整合素构象。在迁移的细胞中，内吞整合素重新组装的FAs向前沿极化，这种极化需要FAK。这些研究确定了FA蛋白在维持内吞整合素活性构象中的意外作用。我们认为整合素的构象记忆增强了脂肪酸的极性重组，使细胞定向迁移。
Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKI gamma)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.