Kops G J, de Ruiter N D, De Vries-Smits A M, Powell D R, Bos J L, Burgering B M
Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht, The Netherlands.
Nature. 1999 Apr 15;398(6728):630-4. doi: 10.1038/19328.
The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B regulates certain insulin-responsive genes, but the transcription factors regulated by protein kinase B have yet to be identified. Genetic analysis in Caenorhabditis elegans has shown that the Forkhead transcription factor daf-16 is regulated by a pathway consisting of insulin-receptor-like daf-2 and PI(3)K-like age-1. Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf-16, both in vitro and in vivo. Inhibition of endogenous PI(3)K and protein kinase B activity prevents protein kinase B-dependent phosphorylation of AFX and reveals residual protein kinase B-independent phosphorylation that requires Ras signalling towards the Ral GTPase. In addition, phosphorylation of AFX by protein kinase B inhibits its transcriptional activity. Together, these results delineate a pathway for PI(3)K-dependent signalling to the nucleus.
磷脂酰肌醇-3-羟基激酶（PI(3)K）效应蛋白激酶B可调节某些胰岛素反应基因，但蛋白激酶B所调节的转录因子尚未得到鉴定。秀丽隐杆线虫的遗传学分析表明，叉头转录因子daf-16受由类胰岛素受体daf-2和类PI(3)K age-1组成的信号通路调控。我们在此表明，蛋白激酶B在体外和体内均可使daf-16的人类同源物AFX发生磷酸化。对内源性PI(3)K和蛋白激酶B活性的抑制可阻止AFX的蛋白激酶B依赖性磷酸化，并揭示了需要Ras向Ral GTP酶发出信号的、与蛋白激酶B无关的残余磷酸化。此外，蛋白激酶B对AFX的磷酸化会抑制其转录活性。这些结果共同描绘了一条PI(3)K依赖性信号向细胞核传递的通路。
