哺乳动物 Ste-20 样激酶 1 和 2 (MST1/2) 是 Hippo 通路的核心丝氨酸-苏氨酸激酶，调节多种细胞过程，包括细胞周期停滞和细胞死亡。在这里，我们在恶性细胞和肿瘤数据集中发现了 MST2 编码基因 STK3 的一种新的选择性剪接变体。这种变体被命名为 STK3Δ7 或 MST2Δ7（分别表示 mRNA 或蛋白质），是由于外显子 7 的跳过而产生的。与全长相比，MST2Δ7 表现出增强的泛素化以及与 E3 泛素蛋白连接酶 CHIP 的相互作用。蛋白质（MST2FL）。 STK3 中的外显子 7 编码激酶结构域内的一个片段，它的排除会损害 MST2 与 MOB（一种主要的 MST1/2 底物）的相互作用和 MOB 的磷酸化。尽管如此，MST2Δ7 能够与 MST1 和 MST2FL 相互作用。与 MST2FL 不同，MST2Δ7 的过度表达不会导致细胞死亡增加和生长停滞。引人注目的是，我们观察到来自多种癌症患者的 3.2-15% 的肿瘤样本中 STK3 外显子 7 被排除，而 STK3Δ7 在健康组织中很少发现。我们的研究发现了一种新型 STK3 剪接变体，该变体会丧失功能，并可能通过影响细胞死亡和静止调节中的 MST2 活性来扰乱组织稳态。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Mammalian Ste-20-like Kinases 1 and 2 (MST1/2) are core serine-threonine kinases of the Hippo pathway regulating several cellular processes, including cell cycle arrest and cell death. Here, we discovered a novel alternative splicing variant of the MST2 encoding gene, STK3, in malignant cells and tumor datasets. This variant, named STK3∆7 or MST2∆7 (for mRNA or protein, respectively), resulted from the skipping of exon 7. MST2∆7 exhibited increased ubiquitylation and interaction with the E3 ubiquitin-protein ligase CHIP compared to the full-length protein (MST2FL). Exon 7 in STK3 encodes a segment within the kinase domain, and its exclusion compromised MST2 interaction with and phosphorylation of MOB, a major MST1/2 substrate. Nevertheless, MST2∆7 was capable of interacting with MST1 and MST2FL. Unlike MST2FL, overexpression of MST2∆7 did not lead to increased cell death and growth arrest. Strikingly, we observed the exclusion of STK3 exon 7 in 3.2-15% of tumor samples from patients of several types of cancer, while STK3∆7 was seldomly found in healthy tissues. Our study identified a novel STK3 splicing variant with loss of function and the potential to disturb tissue homeostasis by impacting on MST2 activities in the regulation of cell death and quiescence.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.