The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status activated by increases in AMP or ADP relative to ATP. Once activated, it phosphorylates targets that promote ATP-generating catabolic pathways or inhibit ATP-consuming anabolic pathways, helping to restore cellular energy balance. Analysis of human cancer genome studies reveals that the PRKAA2 gene (encoding the α2 isoform of the catalytic subunit) is often subject to mis-sense mutations in cancer, particularly in melanoma and non-melanoma skin cancers, where up to 70 mis-sense mutations have been documented, often accompanied by loss of the tumour suppressor NF1. Recently it has been reported that knockout of PRKAA2 in NF1-deficient melanoma cells promoted anchorage-independent growth in vitro, as well as growth as xenografts in immunodeficient mice in vivo, suggesting that AMPK-α2 can act as a tumour suppressor in that context. However, very few of the mis-sense mutations in PRKAA2 that occur in human skin cancer and melanoma have been tested to see whether they cause loss-of-function. We have addressed this by making most of the reported mutations and testing their activity when expressed in AMPK knockout cells. Of 55 different mis-sense mutations (representing 75 cases), 9 (12%) appeared to cause a total loss of activity, 18 (24%) a partial loss, 11 (15%) an increase in phenformin-stimulated kinase activity, while just 37 (49%) had no clear effect on kinase activity. This supports the idea that AMPK-α2 acts as a tumour suppressor in the context of human skin cancer.

中文翻译：

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AMPK-α2 催化亚基频繁发生的功能丧失突变表明在人类皮肤癌中具有抑癌作用

AMP 激活蛋白激酶 (AMPK) 是一种细胞能量状态传感器，通过 AMP 或 ADP 相对于 ATP 的增加而激活。一旦被激活，它就会磷酸化促进 ATP 生成分解代谢途径或抑制 ATP 消耗合成代谢途径的靶标，从而帮助恢复细胞能量平衡。对人类癌症基因组研究的分析表明，PRKAA2 基因（编码催化亚基的 α2 同工型）在癌症中经常发生错义突变，特别是在黑色素瘤和非黑色素瘤皮肤癌中，其中多达 70 个错义突变已被证明，通常伴随着肿瘤抑制因子 NF1 的丧失。最近有报道称，在缺乏 NF1 的黑色素瘤细胞中敲除 PRKAA2 可促进体外贴壁依赖性生长，以及免疫缺陷小鼠体内异种移植物的生长，表明 AMPK-α2 在这种情况下可以充当肿瘤抑制因子。然而，人类皮肤癌和黑色素瘤中发生的 PRKAA2 错义突变很少被测试过是否会导致功能丧失。我们通过制作大部分报告的突变并测试它们在 AMPK 敲除细胞中表达时的活性来解决这个问题。在 55 种不同的错义突变（代表 75 例）中，9 种（12%）似乎导致活性完全丧失，18 种（24%）部分丧失，11 种（15%）导致苯乙双胍刺激的激酶活性增加，而只有 37 例（49%）对激酶活性没有明显影响。这支持了 AMPK-α2 在人类皮肤癌中充当肿瘤抑制因子的观点。