Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation
Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation
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DOI：
10.1046/j.1471-4159.2003.02113.x
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发表时间：
2003-12-01
影响因子：
4.7
通讯作者：
Jope, RS
中科院分区：
文献类型：
--
作者：
Bijur, GN;Jope, RS
我们在此描述了直接影响线粒体的磷脂酰肌醇 3-激酶/Akt 信号通路的新成分。 Akt（蛋白激酶B）首次被证明位于线粒体中，存在于基质和内外膜中，并且线粒体Akt的水平受到非常动态的调节。用胰岛素样生长因子 1、胰岛素或应激（由热休克诱导）刺激多种细胞类型，在刺激后短短几分钟内即可诱导 Akt 易位至线粒体，导致细胞数量增加近 8 至 12 倍，并且线粒体 Akt 处于磷酸化的活性状态。经鉴定，在刺激线粒体 Akt（ATP 合酶的 β 亚基和糖原合酶激酶 3beta）后，两种线粒体蛋白被磷酸化。 Akt 易位至线粒体后，线粒体糖原合酶激酶 3beta 被 Ser9 磷酸化快速且实质性地修饰，从而抑制其活性，这一发现是影响线粒体糖原合酶激酶 3beta 的调节机制的第一个证据。这些结果表明，质膜受体发出的信号或应激产生的信号可快速调节线粒体中的 Akt 和糖原合成酶激酶 3beta。
We describe here a new component of the phosphatidylinositol 3-kinase/Akt signaling pathway that directly impacts mitochondria. Akt (protein kinase B) was shown for the first time to be localized in mitochondria, where it was found to reside in the matrix and the inner and outer membranes, and the level of mitochondrial Akt was very dynamically regulated. Stimulation of a variety of cell types with insulin-like growth factor-1, insulin, or stress (induced by heat shock), induced translocation of Akt to the mitochondria within only several minutes of stimulation, causing increases of nearly eight- to 12-fold, and the mitochondrial Akt was in its phosphorylated, active state. Two mitochondrial proteins were identified to be phosphorylated following stimulation of mitochondrial Akt, the beta-subunit of ATP synthase and glycogen synthase kinase-3beta. The finding that mitochondrial glycogen synthase kinase-3beta was rapidly and substantially modified by Ser9 phosphorylation, which inhibits its activity, following translocation of Akt to the mitochondria is the first evidence for a regulatory mechanism affecting mitochondrial glycogen synthase kinase-3beta. These results demonstrate that signals emanating from plasma membrane receptors or generated by stress rapidly modulate Akt and glycogen synthase kinase-3beta in mitochondria.