Fulton D, Gratton J P, McCabe T J, Fontana J, Fujio Y, Walsh K, Franke T F, Papapetropoulos A, Sessa W C
Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Nature. 1999 Jun 10;399(6736):597-601. doi: 10.1038/21218.
Endothelial nitric oxide synthase (eNOS) is the nitric oxide synthase isoform responsible for maintaining systemic blood pressure, vascular remodelling and angiogenesis. eNOS is phosphorylated in response to various forms of cellular stimulation, but the role of phosphorylation in the regulation of nitric oxide (NO) production and the kinase(s) responsible are not known. Here we show that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eNOS (S1179A) is resistant to phosphorylation and activation by Akt. Moreover, using adenovirus-mediated gene transfer, activated Akt increases basal NO release from endothelial cells, and activation-deficient Akt attenuates NO production stimulated by vascular endothelial growth factor. Thus, eNOS is a newly described Akt substrate linking signal transduction by Akt to the release of the gaseous second messenger NO.
内皮型一氧化氮合酶（eNOS）是负责维持全身血压、血管重塑和血管生成的一氧化氮合酶亚型。eNOS会因各种形式的细胞刺激而发生磷酸化，但磷酸化在一氧化氮（NO）生成调节中的作用以及相关激酶尚不清楚。在此我们表明，丝氨酸/苏氨酸蛋白激酶Akt（蛋白激酶B）可直接使eNOS的丝氨酸1179位点磷酸化并激活该酶，从而导致NO生成，而突变型eNOS（S1179A）对Akt介导的磷酸化和激活具有抗性。此外，利用腺病毒介导的基因转移，激活的Akt可增加内皮细胞的基础NO释放，而激活缺陷型Akt则会减弱血管内皮生长因子刺激的NO生成。因此，eNOS是一种新发现的Akt底物，它将Akt的信号转导与气态第二信使NO的释放联系起来。
