Scrib regulates PAK activity during the cell migration process
Scrib regulates PAK activity during the cell migration process
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DOI：
10.1093/hmg/ddn248
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发表时间：
2008-11-15
影响因子：
3.5
通讯作者：
Santoni, Marie-Josee
中科院分区：
文献类型：
--
作者：
Nola, Sebastien;Sebbagh, Michael;Santoni, Marie-Josee
遗传学研究强调了Scrib在后生动物发育中的关键作用。Scrib的缺乏损害了细胞极性和细胞运动的许多方面，尽管所涉及的机制仍不清楚。在哺乳动物中，Scrib属于一种蛋白质复合物，含有β PIX（Rac/Cdc 42的交换因子）和GIT 1（参与受体再循环和胞吐作用的ARF 6的GT3活化蛋白）。在这里，我们表明，Scrib复合物与PAK，丝氨酸-苏氨酸激酶家族的细胞迁移至关重要。PAK与在heregulin处理的T47 D乳腺癌细胞的前沿的Scrib复合物的成员共定位。我们证明，所需的Scrib复杂的上皮细胞和原代小鼠胚胎成纤维细胞，以有效地应对化学引诱物的线索。在Scrib-deficient细胞中，皮质PAK池减少，从而排除了Rac对其的适当激活。Scrib的丢失也损害了活性Rac在前缘的极化分布，并损害了T47 D细胞和小鼠胚胎成纤维细胞中GTdR的调节活化。这些数据强调了Scrib在细胞迁移中的作用，并显示了Scrib对PAK和Rac功能的强烈影响，PAK和Rac是该过程中涉及的两个关键分子。
Genetic studies have highlighted the key role of Scrib in the development of Metazoans. Deficiency in Scrib impairs many aspects of cell polarity and cell movement although the mechanisms involved remain unclear. In mammals, Scrib belongs to a protein complex containing beta PIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis. Here we show that the Scrib complex associates with PAK, a serine-threonine kinase family crucial for cell migration. PAK colocalizes with members of the Scrib complex at the leading edge of heregulin-treated T47D breast cancer cells. We demonstrate that the Scrib complex is required for epithelial cells and primary mouse embryonic fibroblasts to efficiently respond to chemoattractant cues. In Scrib-deficient cells, the pool of cortical PAK is decreased, thereby precluding its proper activation by Rac. Loss of Scrib also impairs the polarized distribution of active Rac at the leading edge and compromises the regulated activation of the GTPase in T47D cells and mouse embryonic fibroblasts. These data underscore the role of Scrib in cell migration and show the strong impact of Scrib in the function of PAK and Rac, two key molecules implicated in this process.