Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity
Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity
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DOI：
10.1016/s0960-9822(01)00583-8
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发表时间：
2001-11-27
期刊：
影响因子：
9.2
通讯作者：
Brunton, VG
中科院分区：
文献类型：
--
作者：
Timpson, P;Jones, GE;Brunton, VG
背景资料：细胞粘附和移动的能力由细胞粘附/细胞骨架网络的重塑控制，而细胞粘附/细胞骨架网络又由Rho家族的小GTP酶控制。然而，目前尚不清楚在外周肌动蛋白和粘附重塑过程中Rac 1和Cdc 42下游的信号是什么，而这是定向迁移所必需的。我们在这里显示，Rho家族的单个成员RhoA、Rac 1和Cdc 42分别将c-Src酪氨酸激酶的特异性细胞内靶向定向到粘着斑、板状伪足或丝状伪足，并且c-Src（与绿色荧光蛋白偶联的组合的SH 3/SH 2结构域）的衔接子功能足以用于靶向。此外，Src的催化活性是绝对需要在这些外周细胞-基质附着位点重塑，将RhoA依赖性局灶性粘附转化为较小的局灶性复合物沿着Rac 1诱导的板状伪足（或Cdc 42诱导的丝状伪足）。因此，激酶缺陷型c-Src占据外周粘附位点的细胞表现出对迁移刺激的极化受损和运动性降低。此外，磷酸化的FAK，Sro粘附底物，在这些conditions.Conclusions抑制：我们的研究结果表明，个人Rho GTPases指定Src的确切的外周定位和Rac 1和Cdc 42诱导的粘附重塑和定向细胞迁移需要Src活动在外周粘附位点。
Background: The ability of a cell to polarize and move is governed by remodeling of the cellular adhesion/cytoskeletal network that is in turn controlled by the Rho family of small GTPases. However, it is not known what signals lie downstream of Rac1 and Cdc42 during peripheral actin and adhesion remodeling that is required for directional migration.Results: We show here that individual members of the Rho family, RhoA, Rac1, and Cdc42, direct the specific intracellular targeting of c-Src tyrosine kinase to focal adhesions, lamellipodia, or filopodia, respectively, and that the adaptor function of c-Src (the combined SH3/SH2 domains coupled to green fluorescent protein) is sufficient for targeting. Furthermore, Src's catalytic activity is absolutely required at these peripheral cell-matrix attachment sites for remodeling that converts RhoA-dependent focal adhesions into smaller focal complexes along Rac1-induced lamellipodia (or Cdc42-induced filopodia). Consequently, cells in which kinase-deficient c-Src occupies peripheral adhesion sites exhibit impaired polarization toward migratory stimuli and reduced motility. Furthermore, phosphorylation of FAK, an Sro adhesion substrate, is suppressed under these conditions.Conclusions: Our findings demonstrate that individual Rho GTPases specify Src's exact peripheral localization and that Rac1- and Cdc42-induced adhesion remodeling and directed cell migration require Src activity at peripheral adhesion sites.