Par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration.
Par3 and dynein associate to regulate local microtubule dynamics and centrosome orientation during migration.
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DOI：
10.1016/j.cub.2009.05.065
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发表时间：
2009-07-14
期刊：
影响因子：
--
通讯作者：
Gundersen GG
中科院分区：
文献类型：
--
作者：
Schmoranzer J;Fawcett JP;Segura M;Tan S;Vallee RB;Pawson T;Gundersen GG
中心体朝向迁移细胞的前缘的取向取决于动力蛋白和微管（MT）以及前缘的许多信号因子。然而，中心体在成纤维细胞取向过程中保持在细胞中心，这表明在前缘以外的位点工作的因素也可能参与其中。在寻找与动力蛋白在中心体方向上起作用的因素时，我们发现极性蛋白Par 3与动力蛋白相关，并且Par 3的敲低通过破坏中心体在细胞中心的位置来抑制中心体方向，与动力蛋白抑制观察到的表型相同。Par 3通过其N端二聚化和PDZ 1结构域与动力蛋白结合，并与动力蛋白轻链中间链2（LIC 2）特异性相互作用。siRNA敲低LIC 2，但不敲低LIC 1，或过表达LIC 2或Par 3的N-末端结构域，也通过破坏中心体位置来抑制中心体取向。Par 3特异性地定位于伤口边缘成纤维细胞中的细胞-细胞接触，其中它以LIC 2依赖性方式与MT末端和动力蛋白斑点重叠。实时成像显示，与前缘相比，MT在细胞-细胞接触处表现出增加的暂停，并且这种升高的暂停依赖于Par 3和LIC 2。Par 3与动力蛋白相关，并有助于在细胞-细胞接触处局部调节MT动力学和在细胞中心正确定位中心体。我们认为，Par 3作为一个皮质因子，通过与LIC 2-动力蛋白的关联来束缚MT。
Centrosome orientation toward the leading edge of migrating cells depends on dynein and microtubules (MTs) and as well on a number of signaling factors at the leading edge. However, centrosomes are maintained at the cell center during orientation in fibroblasts suggesting that factors working at sites other than the leading edge may also be involved. In a search for factors that function with dynein in centrosome orientation, we found that the polarity protein Par3 associated with dynein and that knockdown of Par3 inhibited centrosome orientation by disrupting the position of the centrosome at the cell center, the same phenotype as that observed with dynein inhibition. Par3 associated with dynein through its N-terminal dimerization and PDZ1 domains, and interacted specifically with dynein light intermediate chain 2 (LIC2). siRNA knockdown of LIC2, but not LIC1, or overexpression of LIC2 or the N-terminal domain of Par3, also inhibited centrosome orientation by disrupting centrosome position. Par3 specifically localized to cell-cell contacts in wound-edge fibroblasts where it overlapped with MT ends and dynein puncta in a LIC2 dependent fashion. Live imaging showed that MTs exhibited increased pausing at cell-cell contacts compared to the leading edge and that this elevated pausing was dependent on Par3 and LIC2. Par3 associates with dynein and contributes to the local regulation of MT dynamics at cell-cell contacts and proper positioning of the centrosome at the cell center. We propose that Par3 acts as a cortical factor that tethers MTs through its association with LIC2-dynein.
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