SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling
SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling
复制标题
DOI：
10.1038/416759a
复制
发表时间：
2002-04-18
期刊：
影响因子：
64.8
通讯作者：
Jessberger, R
中科院分区：
文献类型：
--
作者：
Shinohara, M;Terada, Y;Jessberger, R
磷脂酰肌醇-3-羟基激酶(PI(3)K)在生长因子刺激下被激活，产生脂质第二信使磷脂酰肌醇-3，4，5-三磷酸(PtdIns(3，4，5)P-3)(1-5)。PtdIns(3，4，5)P-3在触发细胞激活、细胞骨架重排、存活和其他反应的信号通路中发挥重要作用。然而，PtdIns(3，4，5)P3的某些靶点尚未发现(1-7)。我们证明了SWAP-70是一种独特的信号蛋白(8-10)，它与PtdIns(3，4，5)P-3特异性结合。在生长因子的刺激下，依赖于PI(3)K但不依赖RAS的细胞质SWAP-70移动到被称为褶皱的细胞膜重排。然而，缺乏与PtdIns(3，4，5)P-3结合能力的突变体SWAP-70可阻断表皮生长因子或血小板衍生生长因子诱导的膜褶皱。SWAP-70与RAC-鸟嘌呤核苷酸交换因子(GEF)同源性低，催化PtdIns(3，4，5)P-3依赖的鸟嘌呤核苷酸交换到RAC。SWAP-70基因缺失的成纤维细胞在表皮生长因子刺激后出现膜皱缩，不能完全激活RAC。我们的结论是，SWAP-70是一种新型的RAC-Global，它独立于RAS，将信号从酪氨酸激酶受体传递到RAC。
Phosphoinositide-3-OH kinase (PI(3) K), activated through growth factor stimulation, generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5) P-3)(1-5). PtdIns(3,4,5) P-3 is instrumantal in signalling pathways that trigger cell activation, cytoskeletal rearrangement, survival and other reactions. However, some targets of PtdIns( 3,4,5) P3 are yet to be discovered(1-7). We demonstrate that SWAP-70, a unique signalling protein(8-10), specifically binds PtdIns(3,4,5) P-3.On stimulation by growth factors, cytoplasmic SWAP-70, which is dependent on PI(3) K but independent of Ras, moved to cell membrane rearrangements known as ruffles. However, mutant SWAP-70 lacking the ability to bind PtdIns(3, 4, 5) P-3 blocked membrane ruffling induced by epidermal growth factor or platelet-derived growth factor. SWAP-70 shows low homology with Rac-guanine nucleotide exchange factors (GEFs), and catalyses PtdIns( 3,4,5) P-3-dependent guanine nucleotide exchange to Rac. SWAP-70-deficient fibroblasts showed impaired membrane ruffling after stimulation with epidermal growth factor, and failed to activate Rac fully. We conclude that SWAP-70 is a new type of Rac-GEF which, independently of Ras, transduces signals from tyrosine kinase receptors to Rac.