Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1
Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1
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DOI：
10.1074/jbc.m605560200
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发表时间：
2006-09-15
影响因子：
4.8
通讯作者：
Capelluto, Daniel G. S.
中科院分区：
文献类型：
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作者：
Finkielstein, Carla V.;Overduin, Michael;Capelluto, Daniel G. S.
Rho鸟苷三磷酸酶(GTP酶)控制细胞的形状和运动，在恶性生长过程中经常过度表达。这些蛋白质充当分子开关，在活跃的GTP结合形式和不活跃的GDP结合形式之间循环。尽管Rho GTP酶通过其异戊二烯基化的C末端固定在膜上，但它在膜和细胞质之间迅速转移。在这里，我们证明了Rho GTP酶rac1通过其多碱基序(PBM)优先与含有磷脂酰丝氨酸(PS)的双层相互作用。Rac1异戊二烯基化有助于膜亲和力，但不是PS识别的关键。然而，类似的蛋白质CDC42(细胞分裂周期42)只有在预基化时才与PS结合。相反，其他Rho GTP酶，如rac2、rac3和RhoA，即使在预基化的情况下也不能与PS结合。PS对细胞的刺激可诱导rac1向质膜移位，并刺激GTP负荷、膜褶皱和丝状足的形成。这种刺激还通过rac1/PS信号通路促进了CDC42的激活和丝裂原激活的蛋白激酶的磷酸化。因此，PBM通过选择性膜磷脂靶向，特异性地指导rac1影响细胞骨架重排和细胞迁移。
dThe Rho guanosine triphosphatases (GTPases) control cell shape and motility and are frequently overexpressed during malignant growth. These proteins act as molecular switches cycling between active GTP- and inactive GDP-bound forms. Despite being membrane anchored via their isoprenylated C-termini, Rho GTPases rapidly translocate between membrane and cytosolic compartments. Here, we show that the Rho GTPase Rac1 preferentially interacts with phosphatidylserine (PS)-containing bilayers through its polybasic motif (PBM). Rac1 isoprenylation contributes to membrane avidity but is not critical for PS recognition. The similar protein Cdc42 (cell division cycle 42), however, only associates with PS when prenylated. Conversely, other Rho GTPases such as Rac2, Rac3, and RhoA do not bind to PS even when they are prenylated. Cell stimulation with PS induces translocation of Rac1 toward the plasma membrane and stimulates GTP loading, membrane ruffling, and filopodia formation. This stimulation also promotes Cdc42 activation and phosphorylation of mitogen-activated protein kinase through Rac1/PS signaling. Consequently, the PBM specifically directs Rac1 to effect cytoskeletal rearrangement and cell migration by selective membrane phospholipid targeting.