Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, setagaya-ku, Tokyo, 156-8502, Japan.
Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, setagaya-ku, Tokyo, 156-8502, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:347-352. doi: 10.1016/j.bbrc.2020.11.079. Epub 2020 Nov 25.
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.
β-连环蛋白是一种多功能蛋白，在调节胚胎发育和组织稳态方面发挥着核心作用。由于β-连环蛋白降解的破坏或β-连环蛋白合成的不受调节，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/精氨酸丰富的剪接因子 9（SRSF9）的过表达通过结合β-连环蛋白 mRNA 并以依赖于雷帕霉素（mTOR）的机制靶标增强其翻译来促进β-连环蛋白的积累。然而，SRSF9 与β-连环蛋白 mRNA 之间相互作用的调节仍不清楚。在这里，我们表明 AMP 激活的蛋白激酶（AMPK）在 RNA 相互作用的 SWQDLKD 基序上对 SRSF9 进行磷酸化，该基序在确定底物特异性方面起着主要作用。AMPK 的磷酸化抑制 SRSF9 与 β-连环蛋白 mRNA 的结合，并抑制由 SRSF9 过表达引起的 β-连环蛋白蛋白合成，而不改变 β-连环蛋白 mRNA 水平。我们的研究结果表明，AMPK 激活剂可能是癌细胞中 SRSF9 衍生的β-连环蛋白过度产生的潜在治疗靶点。
