βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac- mediated Formation of Membrane Protrusion and Cell Motility
βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac- mediated Formation of Membrane Protrusion and Cell Motility
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DOI：
10.1074/jbc.m113.511360
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发表时间：
2014-05-09
影响因子：
4.8
通讯作者：
Daaka, Yehia
中科院分区：
文献类型：
--
作者：
Ma, Xiaojie;Espana-Serrano, Laura;Daaka, Yehia
背景：G蛋白偶联受体（GPCRs）和抑制蛋白已被证明可调节细胞运动。结果如下：Arrestin 1通过RasGRF 2（一种双鸟嘌呤核苷酸交换因子）基因表达和小GTPase Rac活性调节细胞迁移。结论：Arrestin1可能在基因表达水平上调节细胞功能。重要性：Arrestins在转录和翻译后水平上调节细胞迁移，在细胞质和细胞核之间穿梭，并参与G蛋白偶联受体信号转导、肌动蛋白重塑和基因表达。在这里，我们测试的假设，arrestin1调节肌动蛋白重塑和细胞迁移，通过小GT3 Rac。arrestin1的耗竭促进Rac活化，导致多极突起的形成和细胞圆形度的增加，Rac的显性负性形式的过表达逆转了这些形态学变化。小干扰RNA文库筛选将RasGRF2鉴定为arrestin 1的靶标。RasGRF2基因和蛋白表达水平升高后，耗尽arrestin1，和随后的激活Rac的结果在cofilin，可以促进肌动蛋白聚合和多极突起的形成，从而延缓细胞迁移和侵袭的去磷酸化。总之，这些结果表明，arrestin1调节rasgrf2基因表达和Rac激活，影响膜突起和细胞迁移和侵袭。
Background: G protein-coupled receptors (GPCRs) and arrestins have been shown to regulate cell motility. Results: Arrestin1 regulates cell migration through RasGRF2 (a dual guanine nucleotide exchange factor) gene expression and the small GTPase Rac activity. Conclusion: Arrestin1 may regulate cellular functions at the gene expression level. Significance: Arrestins may function at transcriptional and post-translational levels to regulate cell migration.Arrestin proteins shuttle between the cytosol and nucleus and have been shown to regulate G protein-coupled receptor signaling, actin remodeling, and gene expression. Here, we tested the hypothesis that arrestin1 regulates actin remodeling and cell migration through the small GTPase Rac. Depletion of arrestin1 promotes Rac activation, leading to the formation of multipolar protrusions and increased cell circularity, and overexpression of a dominant negative form of Rac reverses these morphological changes. Small interfering RNA library screen identifies RasGRF2 as a target of arrestin1. RasGRF2 gene and protein expression levels are elevated following depletion of arrestin1, and the consequent activation of Rac results in dephosphorylation of cofilin that can promote actin polymerization and formation of multipolar protrusions, thereby retarding cell migration and invasion. Together, these results suggest that arrestin1 regulates rasgrf2 gene expression and Rac activation to affect membrane protrusion and cell migration and invasion.