Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling
Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling
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DOI：
10.1128/mcb.00114-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Fujita, Naoya
中科院分区：
文献类型：
--
作者：
Nakamura, Akito;Naito, Mikihiko;Fujita, Naoya
磷脂酰肌醇3-激酶（PI 3 K）/3-磷脂酰肌醇依赖性蛋白激酶1（PDK 1）/Akt通路调节多种细胞功能，尤其是细胞存活和细胞周期进程。与其他生存途径相比，很少有支架蛋白在该途径中调节信号级联特异性的报道。在这里，我们确定了一个5'阻遏元件下的双重阻遏结合蛋白1（弗洛伊德-1）/Akt激酶相互作用蛋白1（Aki 1）作为一种新的支架PDK 1/Akt途径。Freud-1/Aki 1（也称为CC 2D 1A）表达诱导PDK 1/Akt复合物的形成，并以浓度依赖性的双相方式调节Akt激活。Freud-1/Aki 1也与表皮生长因子（EGF）受体相关，对EGF刺激做出反应，并且是EGF诱导的Akt激活所必需的，但不是胰岛素样生长因子1。Freud-1/Aki 1基因沉默降低Akt激酶活性，导致细胞凋亡诱导和对化疗药物的敏感性增加。我们的研究结果表明，Freud-1/Aki 1是PDK 1/Akt通路的一种新型受体选择性支架蛋白，并提出了一种新的Akt激活机制。
The phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway regulates various cellular functions, especially cell survival and cell cycle progression. In contrast to other survival pathways, there have been few reports of scaffold proteins that regulate signaling cascade specificity in this pathway. Here we identify a 5' repressor element under dual-repression binding protein 1 (Freud-1)/Akt kinase-interacting protein 1 (Aki1) as a novel scaffold for the PDK1/Akt pathway. Freud-1/Aki1 (also known as CC2D1A) expression induced formation of a PDK1/Akt complex and regulated Akt activation in a concentration-dependent biphasic manner. Freud-1/Aki1 also associated with epidermal growth factor (EGF) receptor in response to EGF stimulation and was required for Akt activation induced by EGF, but not by insulin-like growth factor 1. Freud-1/Aki1 gene silencing decreased Akt kinase activity, resulting in induction of apoptosis and increased sensitivity toward chemotherapeutic agents. Our results suggest that Freud-1/Aki1 is a novel receptor-selective scaffold protein for the PDK1/Akt pathway and present a new activation mechanism of Akt.