A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction
A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction
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DOI：
10.1016/s0960-9822(95)00278-8
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发表时间：
1995-12-01
期刊：
影响因子：
9.2
通讯作者：
Waterfield, MD
中科院分区：
文献类型：
--
作者：
Macdougall, LK;Domin, J;Waterfield, MD
背景：哺乳动物磷酸肌醇 3-激酶（PI 3-激酶）参与受体介导的信号转导，并通过其升高细胞磷脂酰肌醇 (3,4,5)-三磷酸的作用参与转化和有丝分裂等过程。此外，已证明产生磷脂酰肌醇 3-磷酸的 PI 3-激酶活性是酵母中蛋白质运输所必需的。结果：我们在果蝇中鉴定了三个不同的 PI 3-激酶家族，使用基于聚合酶链式反应的方法来扩增与 PI 3-激酶保守催化结构域相对应的区域。这些家族成员之一 PI3K_92D 与原型 PI 3 激酶 p110 α 密切相关； PI3K_59F 与 Vps34p 同源，而第三种 PI3K_68D 是一种新型 PI 3 激酶，在整个果蝇生命周期中广泛表达。 Thr PI3K_68D cDNA 编码 210 kDa 的蛋白质，该蛋白质缺乏涉及将 p110 PI 3 激酶连接到 p85 衔接蛋白的序列，但包含可与 SH3 结构域结合的氨基末端富含脯氨酸的序列，以及羧基末端 C2 结构域。生化分析表明，PI3K_68D 在体外具有新的底物特异性，仅限于磷脂酰肌醇和磷脂酰肌醇 4-磷酸，并且不能磷酸化磷脂酰肌醇 (4,5)-二磷酸（p110 的体内底物）。结论：描述了果蝇中的 PI 3-激酶家族，包括以 PI3K_68D 为代表的新类别。 PI3K_68D 具有与含有 SH3 结构域的信号分子结合的潜力，缺乏 p85 接头结合序列，具有不依赖 Ca2+ 的磷脂结合结构域，并显示出有限的体外底物特异性，因此它可以定义一条新的信号转导途径。
Background: Mammalian phosphoinositide 3-kinases (PI 3-kinases) are involved in receptor-mediated signal transduction and have been implicated in processes such as transformation and mitogenesis through their role in elevating cellular phosphatidylinositol (3,4,5)-trisphosphate. Additionally, a PI 3-kinase activity which generates phosphatidylinositol 3-phosphate has been shown to be required for protein trafficking in yeast.Results: We have identified a family of three distinct PI 3-kinases in Drosophila, using an approach based on the polymerase chain reaction to amplify a region corresponding to the conserved catalytic domain of PI 3-kinases. One of these family members, PI3K_92D, is closely related to the prototypical PI 3-kinase, p110 alpha; PI3K_59F is homologous to Vps34p, whereas the third, PI3K_68D, is a novel PI 3-kinase which is widely expressed throughout the Drosophila life cycle. Thr PI3K_68D cDNA encodes a protein of 210 kDa, which lacks sequences implicated in linking p110 PI 3-kinases to p85 adaptor proteins, but contains an amino-terminal proline-rich sequence, which could bind to SH3 domains, and a carboxy-terminal C2 domain. Biochemical analyses demonstrate that PI3K_68D has a novel substrate specificity in vitro, restricted to phosphatidylinositol and phosphatidylinositol 4-phosphate, and is unable to phosphorylate phosphatidylinositol (4,5)-bisphosphate, the implied in vivo substrate for p110.Conclusions: A family of PI 3-kinases in Drosophila, including a novel class represented by PI3K_68D, is described. PI3K_68D has the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-binding sequences, has a Ca2+-independent phospholipid-binding domain and displays a restricted in vitro substrate specificity, so it could define a novel signal transduction pathway.