Insulin receptor substrate 1 is a substrate of the Pim protein kinases.
Insulin receptor substrate 1 is a substrate of the Pim protein kinases.
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DOI：
10.18632/oncotarget.7918
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发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Kraft AS
中科院分区：
文献类型：
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作者：
Song JH;Padi SK;Luevano LA;Minden MD;DeAngelo DJ;Hardiman G;Ball LE;Warfel NA;Kraft AS
丝氨酸/苏氨酸蛋白激酶的Pim家族（Pim 1、2和3）通过调节葡萄糖代谢、蛋白质合成和线粒体氧化磷酸化来促进细胞转化。靶向Pim蛋白激酶的药物正在I/II期临床试验中进行测试，用于治疗造血系统恶性肿瘤。这些研究的目的是鉴定Pim底物，这些底物可以帮助定义这些酶调节的途径，并可能作为Pim活性的生物标志物。为了鉴定新的底物，进行了生物信息学分析以鉴定含有共有Pim磷酸化位点的蛋白质。该分析鉴定了胰岛素受体底物1和2（IRS 1/2）作为潜在的Pim底物。在I期试验的组织培养、动物和人类样本中进行实验，以验证这一观察结果并定义这种磷酸化的生物学读数。我们的研究表明，在恶性和正常细胞中，使用Pim激酶的遗传或药理学抑制或该家族酶的过表达，人IRS 1 S1101和IRS 2S 1149是Pim底物。在异种移植肿瘤实验和人类I期临床试验中，对动物或人类体内施用的泛Pim抑制剂降低了肿瘤组织中的IRS 1 S1101磷酸化。这种磷酸化被证明对IRS蛋白家族的半衰期有影响，表明在胰岛素或IGF信号传导中的作用。这些结果表明，IRS 1 S1101是Pim激酶的新型底物，并为评价Pim抑制剂治疗提供了新型标志物。
The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.