Identification of a novel alternative splicing isoform of the Hippo kinase STK3/MST2 with impaired tumor suppressor activities

Abstract 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). The exon 7 in STK3 encodes a segment within the kinase domain, and its exclusion compromised interaction of MST2∆7 with MOB, a major MST1/2 substrate. Unlike MST2FL, overexpression of MST2∆7 did not lead to increased cell death and growth arrest. Strikingly, we observed 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 that we analyzed. Our study identified a novel STK3 splicing variant with loss-of-function and potential to disturb tissue homeostasis by impacting the tumor suppressor activities of MST2 in regulation of cell death and quiescence.