Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
Dev Cell. 2013 Mar 11;24(5):472-85. doi: 10.1016/j.devcel.2013.01.027. Epub 2013 Feb 28.
Precise spatiotemporal coordination of integrin adhesion complex dynamics is essential for efficient cell migration. For cells adherent to fibronectin, differential engagement of α5β1 and αVβ3 integrins is used to elicit changes in adhesion complex stability, mechanosensation, matrix assembly, and migration, but the mechanisms responsible for receptor regulation have remained largely obscure. We identify phosphorylation of the membrane-intercalated proteoglycan syndecan-4 as an essential switch controlling integrin recycling. Src phosphorylates syndecan-4 and, by driving syntenin binding, leads to suppression of Arf6 activity and recycling of αVβ3 to the plasma membrane at the expense of α5β1. The resultant elevation in αVβ3 engagement promotes stabilization of focal adhesions. Conversely, abrogation of syndecan-4 phosphorylation drives surface expression of α5β1, destabilizes adhesion complexes, and disrupts cell migration. These data identify the dynamic spatiotemporal regulation of Src-mediated syndecan-4 phosphorylation as an essential switch controlling integrin trafficking and adhesion dynamics to promote efficient cell migration.
整合素黏附复合物动力学的精确时空协调对于有效的细胞迁移至关重要。对于黏附于纤维连接蛋白的细胞，α5β1 和 αVβ3 整合素的差异结合被用来引发黏附复合物稳定性、机械敏感性、基质组装和迁移的变化，但负责受体调节的机制在很大程度上仍不清楚。我们发现跨膜蛋白聚糖 syndecan-4 的磷酸化是控制整合素循环的关键开关。Src 磷酸化 syndecan-4，并通过驱动 syntenin 结合，导致 Arf6 活性的抑制和 αVβ3 向质膜的循环，而牺牲 α5β1。由此引起的 αVβ3 结合的增加促进了粘着斑的稳定。相反，syndecan-4 磷酸化的消除导致 α5β1 的表面表达，破坏黏附复合物，并破坏细胞迁移。这些数据表明 Src 介导的 syndecan-4 磷酸化的动态时空调节是控制整合素运输和黏附动力学以促进有效细胞迁移的关键开关。
