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首页> 外文期刊>Molecular and Cellular Biology >Mutation of the PDK1 PH Domain Inhibits Protein Kinase B/Akt, Leading to Small Size and Insulin Resistance
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Mutation of the PDK1 PH Domain Inhibits Protein Kinase B/Akt, Leading to Small Size and Insulin Resistance

机译：PDK1 PH域的突变抑制蛋白激酶B / Akt，导致体积小和胰岛素抵抗

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摘要

PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.
机译：PDK1激活一组激酶，包括蛋白激酶B（PKB）/ Akt，p70核糖体S6激酶（S6K）以及血清和糖皮质激素诱导的蛋白激酶（SGK），这些激酶介导许多胰岛素作用以及其他激动剂。 PDK1通过pleckstrin同源性（PH）域与磷酸肌醇相互作用。为了研究这种相互作用的作用，我们生成了敲入小鼠，它们表达了不能结合磷酸肌醇的PDK1突变体。敲入的小鼠非常小，具有胰岛素抵抗和高胰岛素血症。在敲入小鼠中，PKB的活化显着降低，这是由于Thr308处PKB的磷酸化程度降低，该残基被PDK1磷酸化。这导致下游mTOR复合物1和S6K1信号通路的抑制。相反，通过进食诱导的SGK1或p90核糖体S6激酶的激活或S6K1的刺激不受PDK1 PH域突变的影响。这些发现确立了PDK1-磷酸肌醇相互作用的重要性，从而使PKB能够被动物模型有效激活。我们的发现揭示了减少的PKB亚型激活如何影响下游信号通路，从而导致大小以及胰岛素抵抗的降低。

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