ZAK is a novel mixed lineage kinase-like protein that contains a leucine-zipper and a sterile-alpha motif as a protein-protein interaction domain, and it is located in the cytoplasm. There are 2 alternatively spliced forms of ZAK: ZAKα and ZAKβ. Previous studies showed that ZAKα is involved in various cell processes, including cell proliferation, cell differentiation, and cardiac hypertrophy, but the molecular mechanism of ZAKβ is not yet known. In a recent study in our laboratory, we found that ZAKβ can ameliorate the apoptotic effect induced by ZAKα in H9c2 cells. We further hypothesized that ZAKβ could also improve the apoptotic effect induced by ZAKα in human osteosarcoma cells. The results of this study show that ZAKβ can induce apoptosis and decrease cell viability similar to the effects of ZAKα. Interestingly, our ZAKα-specific inhibitor assay shows that the expression of ZAKβ is highly dependent on ZAKα expression. However, ZAKβ expression effectively induces ZAKα expression and results in synergistic enhancement of apoptosis in human osteosarcoma cells. Furthermore, co-immunoprecipitation results revealed that ZAKα can directly interact with ZAKβ, and this interaction may contribute to the enhanced apoptotic effects.
Significance of the study: ZAK is a mixed lineage kinase involved in cell differentiation, proliferation, and hypertrophic growth. ZAKα isoform of ZAK is associated with tumorigenesis, but the function of ZAKβ is not yet known. In H9c2 cells, ZAKβ was found to ameliorate the apoptotic effect induced by ZAKα. However, in osteosarcoma cells, ZAKβ elevates the apoptotic effect induced by ZAKα. In this study, we show that similar to ZAKα, the ZAKβ induces apoptosis and decreases cell viability. Interestingly, the expression of ZAKβ is dependent on ZAKα expression, and ZAKβ further enhances ZAKα expression and results in synergistic enhancement of apoptosis in osteosarcoma cells.
Keywords: ZAKα; ZAKβ; apoptotic effect; osteosarcoma; sterile-alpha motif.
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