ACTIVATION OF PHOSPHOINOSITIDE 3-KINASE IS REQUIRED FOR PDGF-STIMULATED MEMBRANE RUFFLING
ACTIVATION OF PHOSPHOINOSITIDE 3-KINASE IS REQUIRED FOR PDGF-STIMULATED MEMBRANE RUFFLING
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DOI：
10.1016/s0960-9822(00)00087-7
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发表时间：
1994-05-01
期刊：
影响因子：
9.2
通讯作者：
STEPHENS, L
中科院分区：
文献类型：
--
作者：
WENNSTROM, S;HAWKINS, P;STEPHENS, L
背景：大量证据表明，磷脂酰肌醇3-激酶(PI-3-Kinase)是多种哺乳动物生长因子和其他激素的细胞表面受体所使用的信号通路的重要组成部分。这种酶的生理产物是一种被称为磷脂酰肌醇(3，4，5)-三磷酸的高极性膜脂，这种脂类被认为是细胞中的第二信使，但其可能的作用靶点尚不清楚。结果：培养的猪主动脉内皮细胞表达的PDGFβ受体激活，引起肌动蛋白细丝的特殊重排，导致膜皱折。我们已经发现，PDGFβ受体激活的这一结果被三个独立的PI 3-激酶活性操纵所抑制：第一，通过删除与PI 3-激酶结合的PDGFβ-受体中的酪氨酸残基，第二，通过过表达突变的85kD PI 3-激酶调节亚基，而催化激酶亚基不能与之结合；结论：这些结果有力地证明了生长因子刺激的猪主动脉内皮细胞膜皱折所需的磷脂酰肌醇(3，4，5)-三磷酸的合成，并提示这种脂质的合成可能是导致小GTP结合蛋白RAC直接或间接激活的信号通路的一部分。
Background: There is substantial evidence that phosphoinositide 3-kinase (PI 3-kinase) is a critical component of signalling pathways used by the cell-surface receptors for a variety of mammalian growth factors and other hormones. The physiological product of this enzyme is a highly polar membrane lipid called phosphatidylinositol (3,4,5)-trisphosphate This lipid has been postulated to act as a second-messenger in cells but its putative targets are still unknown.Results: A particular rearrangement of actin filaments, which results in membrane ruffling, is elicited by the activation of PDGF beta-receptors expressed in cultured porcine aortic endothelial cells. We have found that this consequence of PDGF beta-receptor activation is inhibited by three independent manipulations of PI 3-kinase activity: firstly, by the deletion of tyrosine residues in the PDGF beta-receptor to which PI 3-kinase binds; secondly, by the overexpression of a mutant 85 kD PI 3-kinase regulatory subunit to which the catalytic kinase subunit cannot bind; and thirdly, by the addition of the fungal metabolite wortmannin, which is a potent inhibitor of the catalytic activity of PI 3-kinase.Conclusions: These results argue strongly that phosphatidylinositol (3,4,5)-trisphosphate synthesis is required for growth-factor-stimulated membrane ruffling in porcine aortic endothelial cells, and suggest that synthesis of this lipid may be part of a signalling pathway leading to direct or indirect activation of the small GTP-binding protein Rac.