Members of the protein kinase D (PKD) family (PKD1, 2, and 3) integrate hormonal and nutritional inputs to regulate complex cellular metabolism. Despite the fact that a number of functions have been annotated to particular PKDs, their molecular targets are relatively poorly explored. PKD3 promotes insulin sensitivity and suppresses lipogenesis in the liver of animals fed a high-fat diet. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified more than 300 putative targets of PKD3. Furthermore, biochemical analysis revealed that PKD3 regulates cAMP-dependent PKA activity, a master regulator of the hepatic response to glucagon and fasting. PKA regulates glucose, lipid, and amino acid metabolism in the liver, by targeting key enzymes in the respective processes. Among them the PKA targets phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Consistently, we showed that PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Therefore, our data indicate that PKD3 might play a role in the hepatic response to glucagon.

中文翻译：

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磷酸化蛋白质组学方法表明 PKD3 控制 PKA 介导的葡萄糖和酪氨酸代谢。

蛋白激酶 D (PKD) 家族的成员（PKD1、2 和 3）整合激素和营养输入来调节复杂的细胞代谢。尽管许多功能已被注释到特定的 PKD，但对它们的分子靶点的探索相对较少。PKD3 促进胰岛素敏感性并抑制高脂肪饮食动物肝脏中的脂肪生成。然而，它的底物在很大程度上是未知的。在这里，我们应用蛋白质组学方法来确定 PKD3 目标。我们确定了 300 多个 PKD3 的假定目标。此外，生化分析表明，PKD3 调节 cAMP 依赖性 PKA 活性，这是肝脏对胰高血糖素和禁食反应的主要调节因子。PKA 通过靶向各个过程中的关键酶来调节肝脏中的葡萄糖、脂质和氨基酸代谢。其中PKA靶向苯丙氨酸羟化酶（PAH）催化苯丙氨酸转化为酪氨酸。一致地，我们表明 PKD3 被胰高血糖素激活并促进肝细胞中的葡萄糖和酪氨酸水平。因此，我们的数据表明 PKD3 可能在肝脏对胰高血糖素的反应中发挥作用。