Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane
Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane
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DOI：
10.1091/mbc.e07-04-0337
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发表时间：
2008-07-01
影响因子：
3.3
通讯作者：
Ryu, Sung Ho
中科院分区：
文献类型：
--
作者：
Chae, Young Chan;Kim, Jung Hwan;Ryu, Sung Ho
小GTPase Rac是肌动蛋白细胞骨架重排的重要调控因子，在细胞扩散、迁移、有丝分裂、吞噬、超氧化物生成和轴突生长等过程中发挥重要作用。一般认为Rac活性受三磷酸鸟苷(GTP)/二磷酸鸟苷（GDP）循环的调控。但是，研究表明，除了Rac-GTP负载外，膜定位对于下游效应信号的启动也是必需的。然而，控制GTP-Rac靶向质膜的分子机制在很大程度上仍然未知。在这里，我们发现了一条将磷脂酶D （PLD）与Rac1的局部功能联系起来的信号通路。我们发现PLD产物磷脂酸（PA）作为Rac1的膜锚。Rac1的c端多基基序负责与PA的直接相互作用，在该区域突变的Rac1无法转运到质膜上，也无法在整合素激活时激活下游靶p21活化的激酶。最后，我们发现PA诱导红鸟嘌呤核苷酸解离抑制剂与Rac1分离，并且PA介导的Rac1定位对整合素介导的板足形成、细胞扩散和迁移很重要。这些结果为通过提高PLD活性来定位GTP-Rac1提供了一种新的分子机制，并提示了多种细胞功能所需的一般机制
Small GTPase Rac is a crucial regulator of actin cytoskeletal rearrangement, and it plays an important role in cell spreading, migration, mitogenesis, phagocytosis, superoxide generation, and axonal growth. It is generally accepted that Rac activity is regulated by the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle. But, it is suggested that in addition to Rac-GTP loading, membrane localization is required for the initiation of downstream effector signaling. However, the molecular mechanisms that control the targeting of GTP-Rac to the plasma membrane remain largely unknown. Here, we have uncovered a signaling pathway linking phospholipase D (PLD) to the localized functions of Rac1. We show that PLD product phosphatidic acid (PA) acts as a membrane anchor of Rac1. The C-terminal polybasic motif of Rac1 is responsible for direct interaction with PA, and Rac1 mutated in this region is incapable of translocating to the plasma membrane and of activating downstream target p21-activated kinase upon integrin activation. Finally, we show that PA induces dissociation of Rho-guanine nucleotide dissociation inhibitor from Rac1 and that PA-mediated Rac1 localization is important for integrin-mediated lamellipodia formation, cell spreading, and migration. These results provide a novel molecular mechanism for the GTP-Rac1 localization through the elevating PLD activity, and they suggest a general mechanism for diverse cellular functions that is required