Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia.
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Elife. 2021 Jul 13;10:e66942. doi: 10.7554/eLife.66942.
The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which is indicative of negative feedback operating on acute timescales. Here, we show that Akt itself engages this negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Phosphorylation results in the depletion of plasma membrane-localised IRS1/2, reducing the pool available for interaction with the insulin receptor. Together these events limit plasma membrane-associated PI3K and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. We identified two Akt-dependent phosphorylation sites in IRS2 at S306 (S303 in mouse) and S577 (S573 in mouse) that are key drivers of this negative feedback. These findings establish a novel mechanism by which the kinase Akt acutely controls PIP3 abundance, through post-translational modification of the IRS scaffold.
磷酸肌醇 3-激酶 (PI3K)-Akt 网络受到反馈机制的严格控制，这些反馈机制调节信号流并确保信号保真度。先前已经报道了胰岛素刺激下 Akt 快速超调至质膜的募集，这表明在急性时间尺度上存在负反馈作用。在这里，我们表明 Akt 本身通过磷酸化胰岛素受体底物 (IRS) 1 和 2 上的多个残基来参与这种负反馈。磷酸化导致质膜定位的 IRS1/2 耗竭，减少了与胰岛素受体相互作用的可用池。这些事件共同限制了质膜相关的 PI3K 和磷脂酰肌醇 (3,4,5)-三磷酸 (PIP3) 的合成。我们在 IRS2 中鉴定了两个 Akt 依赖性磷酸化位点，S306（在小鼠中为 S303）和 S577（在小鼠中为 S573），它们是这种负反馈的关键驱动因素。这些发现通过 IRS 支架的翻译后修饰，确立了激酶 Akt 急性控制 PIP3 丰度的新机制。
