dSTK10 maintains tissue homeostasis by preventing JNK-mediated apoptosis

Abstract

Abstract Background The c-Jun N-terminal kinase (JNK) pathway is an evolutionarily conserved regulator of cell death, which is essential for coordinating tissue homeostasis. In this study, we have characterized the Drosophila Ste20-like kinase dSTK10 as a novel modulator of JNK pathway-mediated apoptotic cell death. Results First, ectopic JNK signaling-triggered cell death is enhanced in heterozygous dSTK10 mutants, and suppressed by dSTK10 overexpression. Second, depletion of dSTK10 activates JNK signaling, which results in enhanced apoptosis and impaired tissue homeostasis. In addition, genetic epistasis analysis suggests that dSTK10 acts upstream of or in parallel to Hep to regulate JNK-mediated apoptotic cell death. Moreover, dSTK10 is necessary and sufficient for preventing physiologic JNK signaling-mediated cell death in development. Furthermore, introduction of STK10, the human ortholog of dSTK10, into Drosophila restores dSTK10 depletion-induced cell death and compromised tissue homeostasis. Lastly, knockdown of STK10 in human cancer cells also leads to JNK activation. Conclusions Thus, this study has uncovered an evolutionarily conserved role of dSTK10/STK10 in blocking JNK signaling, which is required for cell death inhibition and tissue homeostasis maintenance in Drosophila development.