Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway
Drosophila phosphoinositide-dependent kinase-1 regulates apoptosis and growth via the phosphoinositide 3-kinase-dependent signaling pathway
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DOI：
10.1073/pnas.101596998
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发表时间：
2001-05-22
影响因子：
11.1
通讯作者：
Chung, J
中科院分区：
文献类型：
--
作者：
Cho, KS;Lee, JH;Chung, J
磷酸肌醇依赖性激酶 1 (PDK-1) 是磷酸肌醇 3 激酶 (PI3K) 和各种细胞内丝氨酸/苏氨酸激酶（包括 Akt/蛋白激酶 B (PKB)、p70 56 激酶和蛋白激酶 C）之间细胞信号转导的中心介质。最近的细胞转染实验研究表明，PDK-1 可能是 参与多种细胞功能，包括细胞生长和凋亡。然而，尽管 PDK-1 在细胞信号转导中发挥着关键作用，但其在多细胞系统中的体内功能却很少被研究。在这里，我们分离了果蝇PDK-1 (dPDK-1)突变体并表征了该激酶的体内作用，dPDK-1基因缺陷的果蝇在胚胎阶段表现出致死性和凋亡表型。相反，dPDK-1 的过度表达以果蝇 PI3K 依赖性方式增加了细胞和器官的大小。 dPDK-1不仅可以激活果蝇Akt/PKB（Dakt1），还可以替代其哺乳动物直系同源物的体内功能来激活Akt/PKB，dPDK-1和Dakt1之间的这种功能相互作用通过果蝇的遗传分析得到进一步证实。另一方面，cAMP依赖性蛋白激酶被认为是dPDK-1的可能靶标，但它不与dPDK-1相互作用。总之，我们的研究结果提供了直接证据，表明 dPDK-1 通过 PI3K 依赖性信号通路调节果蝇发育过程中的细胞生长和凋亡，并证明我们的果蝇系统是阐明 PDK-1 体内功能和靶标的强大工具。
Phosphoinositide-dependent kinase-1 (PDK-1) is a central mediator of the cell signaling between phosphoinositide 3-kinase (PI3K) and various intracellular serine/threonine kinases including Akt/protein kinase B (PKB), p70 56 kinases, and protein kinase C, Recent studies with cell transfection experiments have implied that PDK-1 may be involved in various cell functions including cell growth and apoptosis, However, despite its pivotal role in cellular signalings, the in vivo functions of PDK-1 in a multicellular system have rarely been investigated. Here, we have isolated Drosophila PDK-1 (dPDK-1) mutants and characterized the in vivo roles of the kinase, Drosophila deficient in the dPDK-1 gene exhibited lethality and an apoptotic phenotype in the embryonic stage. Conversely, overexpression of dPDK-1 increased cell and organ size in a Drosophila PI3K-dependent manner. dPDK-1 not only could activate Drosophila Akt/PKB (Dakt1), but also substitute the in vivo functions of its mammalian ortholog to activate Akt/PKB, This functional interaction between dPDK-1 and Dakt1 was further confirmed through genetic analyses in Drosophila. On the other hand, cAMP-dependent protein kinase, which has been proposed as a possible target of dPDK- I, did not interact with dPDK-1. In conclusion, our findings provide direct evidence that dPDK-1 regulates cell growth and apoptosis during Drosophila development via the PI3K-dependent signaling pathway and demonstrate our Drosophila system to be a powerful tool for elucidating the in vivo functions and targets of PDK-1.