磷脂酰肌醇-3激酶与丙酮酸脱氢酶激酶1的联系：不仅仅是通往蛋白激酶B的一条途径。
The PI3K-PDK1 connection: more than just a road to PKB.
作者信息
Vanhaesebroeck B, Alessi D R
机构信息
Cell Signalling Group, Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, U.K.
出版信息
Biochem J. 2000 Mar 15;346 Pt 3(Pt 3):561-76.
Abstract
Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase. We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB.
摘要
磷脂酰肌醇3激酶（PI3Ks）可生成特定的肌醇脂质，这些脂质与细胞生长、增殖、存活、分化及细胞骨架变化的调控有关。PI3K脂质产物最具特征的靶点之一是蛋白激酶Akt或蛋白激酶B（PKB）。在静止细胞中，PKB以低活性构象存在于细胞质中。细胞受到刺激后，PKB通过PI3K脂质产物募集至细胞膜并被3'-磷酸肌醇依赖性激酶-1（PDK1）磷酸化而被激活。在此，我们综述PKB被激活的机制以及这种多功能激酶的下游作用。我们还讨论了PDK1可能参与除PKB之外的蛋白激酶激活的证据、PDK1这种活性可能被调控的机制，以及一些目前假定为PKB底物靶点的蛋白实际上可能被除PKB之外的PDK1调控激酶磷酸化的可能性。
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本文引用的文献
1
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Oncogene. 1999 Dec 23;18(56):8024-32. doi: 10.1038/sj.onc.1203258.
2
Evidence that 3-phosphoinositide-dependent protein kinase-1 mediates phosphorylation of p70 S6 kinase in vivo at Thr-412 as well as Thr-252.有证据表明，3-磷酸肌醇依赖性蛋白激酶-1在体内介导p70 S6激酶在苏氨酸-412以及苏氨酸-252处的磷酸化。
J Biol Chem. 1999 Dec 24;274(52):37400-6. doi: 10.1074/jbc.274.52.37400.
3
Signaling by distinct classes of phosphoinositide 3-kinases.不同类别的磷酸肌醇3激酶的信号传导
Exp Cell Res. 1999 Nov 25;253(1):239-54. doi: 10.1006/excr.1999.4701.
4
Phosphorylation and regulation of Raf by Akt (protein kinase B).Akt（蛋白激酶B）对Raf的磷酸化作用及调控
Science. 1999 Nov 26;286(5445):1741-4. doi: 10.1126/science.286.5445.1741.
5
Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.Akt对Raf-MEK-ERK信号通路的分化阶段特异性抑制作用。
Science. 1999 Nov 26;286(5445):1738-41. doi: 10.1126/science.286.5445.1738.
6
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Mol Cell Biol. 1999 Dec;19(12):8344-52. doi: 10.1128/MCB.19.12.8344.
7
Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro.免疫纯化的雷帕霉素哺乳动物靶标在体外磷酸化并激活p70 S6激酶α。
J Biol Chem. 1999 Nov 26;274(48):34493-8. doi: 10.1074/jbc.274.48.34493.
8
9
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10
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