TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila development

Transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1) is a m ember of the MAPKKK superfamily and has been characterized as a component o f the TGF-beta/bone morphogenetic protein signaling pathway. TAK1 function has been extensively studied in cultured cells, but its in vivo function is not fully understood. In this study, we isolated a Drosophila homolog of T AK1 (dTAK1) which contains an extensively conserved NH2-terminal kinase dom ain and a partially conserved COOH-terminal domain. To learn about possible endogenous roles of TAK1 during animal development, we generated transgeni c flies which express dTAK1 or the mouse TAK1 (mTAK1) gene in the fly visua l system. Ectopic activation of TAK1 signaling leads to a small eye phenoty pe, and genetic analysis reveals that this phenotype is a result of ectopic ally induced apoptosis. Genetic and biochemical analyses also indicate that the c-Jun amino-terminal kinase (JNK) signaling pathway is specifically ac tivated by TAK1 signaling. Expression of a dominant negative form of dTAK d uring embryonic development resulted in various embryonic cuticle defects i ncluding dorsal open phenotypes. Our results strongly suggest that in Droso phila melanogaster, TAK1 functions as a MAPKKK in the JNK signaling pathway and participates in such diverse roles as control of cell shape and regula tion of apoptosis.