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首页> 外文期刊>Molecular and Cellular Biology >Type I Phosphatidylinositol Phosphate Kinase Beta Regulates Focal Adhesion Disassembly by Promoting β1 Integrin Endocytosis
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Type I Phosphatidylinositol Phosphate Kinase Beta Regulates Focal Adhesion Disassembly by Promoting β1 Integrin Endocytosis

机译：I型磷脂酰肌醇磷酸激酶Beta通过促进β1整联蛋白内吞作用来调节局灶性粘连解离

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摘要

Cell migration requires the regulated disassembly of focal adhesions, but the underlying mechanisms remain poorly defined. We have previously shown that focal adhesion disassembly requires the dynamin 2- and clathrin-dependent endocytosis of ligand-activated β1 integrins. Here, we identify type I phosphatidylinositol phosphate kinase beta (PIPKIβ), an enzyme that generates phosphatidylinositol-4,5-bisphosphate (PI4,5P2), as a key regulator of this process. We found that knockdown of PIPKIβ by RNA interference blocks the internalization of active β1 integrins and impairs focal adhesion turnover and cell migration. These defects are caused by the failure to target the endocytic machinery, including clathrin adaptors and dynamin 2, to focal adhesion sites. As a consequence, depletion of PIPKIβ blocks clathrin assembly at adhesion plaques and prevents complex formation between dynamin 2 and focal adhesion kinase (FAK), a critical step in focal adhesion turnover. Together, our findings identify PIPKIβ as a novel regulator of focal adhesion disassembly and suggest that PIPKIβ spatially regulates integrin endocytosis at adhesion sites to control cell migration.
机译：细胞迁移需要调节粘着斑的拆卸，但其潜在机制仍不清楚。先前我们已经表明，粘着斑的拆卸需要配体活化的β1整联蛋白的动力蛋白2和网格蛋白依赖性内吞作用。在这里，我们确定I型磷脂酰肌醇磷酸激酶β（PIPKIβ）是该过程的关键调节剂，该酶可生成磷脂酰肌醇-4,5-双磷酸酯（PI4,5P 2 ）。我们发现，RNA干扰敲低PIPKIβ会阻止活性β1整合素的内在化，并损害粘着斑更新和细胞迁移。这些缺陷是由于未能将包括网格蛋白衔接子和动力蛋白2在内的内吞机器靶向粘着部位所致。结果，PIPKIβ的耗竭会阻止网格蛋白在黏附斑处的组装，并阻止动力蛋白2和黏着斑激酶（FAK）之间形成复杂的复合物，这是黏着斑更新的关键步骤。在一起，我们的发现确定PIPKIβ是粘着斑拆卸的新型调节剂，并表明PIPKIβ在空间上调节粘附位点的整联蛋白内吞作用，以控制细胞迁移。

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