AMP-activated protein kinase regulates β-catenin protein synthesis by phosphorylating serine/arginine-rich splicing factor 9
AMP-activated protein kinase regulates β-catenin protein synthesis by phosphorylating serine/arginine-rich splicing factor 9
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AMP 激活的蛋白激酶通过磷酸化富含丝氨酸/精氨酸的剪接因子 9 来调节 β-连环蛋白的合成
DOI：
10.1016/j.bbrc.2020.11.079
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发表时间：
2021
影响因子：
3.1
通讯作者：
Suzuki Tsukasa
中科院分区：
文献类型：
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作者：
Matsumoto Eri;Matsumoto Yu;Inoue Jun;Yamamoto Yuji;Suzuki Tsukasa
β-连环蛋白是一种多功能蛋白质，在调节胚胎发育和组织稳态中起核心作用。由于β-连环蛋白降解被破坏或β-连环蛋白合成不受调节，β-连环蛋白的异常积累导致癌症的发展。最近的一项研究表明，原癌基因丝氨酸/丝氨酸丰富的剪接因子9（SRSF 9）的过表达通过结合β-catenin mRNA并以依赖于雷帕霉素（mTOR）的机制靶点的方式增强其翻译来促进β-catenin积累。然而，SRSF 9与β-catenin mRNA之间的相互作用的调控尚不清楚。在这里，我们表明，AMP激活的蛋白激酶（AMPK）磷酸化SRSF 9在RNA相互作用的SWQDLKD基序，发挥了重要作用，在确定底物特异性。AMPK的磷酸化抑制了SRSF 9与β-catenin mRNA的结合，并抑制了由SRSF 9过表达引起的β-catenin蛋白合成，而不改变β-catenin mRNA水平。我们的研究结果表明，AMPK激活剂是SRSF 9衍生的β-连环蛋白在癌细胞中过度产生的潜在治疗靶点。
β-catenin is a multi-functional protein with a central role in regulating embryonic development and tissue homeostasis. The abnormal accumulation of β-catenin, due to disrupted β-catenin degradation or unregulated β-catenin synthesis, causes the development of cancer. A recent study showed that the overexpression of proto-oncogene serine/arginine-rich splicing factor 9 (SRSF9) promotes β-catenin accumulation via binding β-catenin mRNA and enhancing its translation in a manner that is dependent on the mechanistic target of rapamycin (mTOR). However, the regulation of the interaction between SRSF9 and mRNA of β-catenin remains unclear. Here, we show that AMP-activated protein kinase (AMPK) phosphorylates SRSF9 at the RNA-interacting SWQDLKD motif that plays a major role in determining substrate specificity. The phosphorylation by AMPK inhibits the binding of SRSF9 to β-catenin mRNA and suppresses β-catenin protein synthesis caused by SRSF9 overexpression without changing the β-catenin mRNA levels. Our findings suggest that AMPK activators are potential therapeutic targets for SRSF9-derived overproduction of β-catenin in cancer cells.