TAK1 Participates in c-Jun N-Terminal Kinase Signaling during Drosophila Development

Abstract

Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) is a member of the MAPKKK superfamily and has been characterized as a component of the TGF-β/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 aDrosophila homolog of TAK1 (dTAK1) which contains an extensively conserved NH₂-terminal kinase domain and a partially conserved COOH-terminal domain. To learn about possible endogenous roles of TAK1 during animal development, we generated transgenic flies which express dTAK1 or the mouseTAK1 (mTAK1) gene in the fly visual system. Ectopic activation of TAK1 signaling leads to a small eye phenotype, and genetic analysis reveals that this phenotype is a result of ectopically induced apoptosis. Genetic and biochemical analyses also indicate that the c-Jun amino-terminal kinase (JNK) signaling pathway is specifically activated by TAK1 signaling. Expression of a dominant negative form of dTAK during embryonic development resulted in various embryonic cuticle defects including dorsal open phenotypes. Our results strongly suggest that in Drosophila melanogaster, TAK1 functions as a MAPKKK in the JNK signaling pathway and participates in such diverse roles as control of cell shape and regulation of apoptosis.

ACKNOWLEDGMENTS

Y. Takatsu and M. Nakamura contributed equally to this work.

We are grateful to N. Nakamura and K. Nakagawa for experimental help. We also thank A. Kreuz and T. Tanimura for comments on the manuscript; T. Adachi-Yamada and K. Sawamoto for fly stocks and technical advice; S. Goto for the UAS-hep construct; H. Steller forrpr and hid cDNAs; N. Patel for Elav antibody; T. Adachi-Yamada for anti-p-D-p38b antibody; and K. Basler, D. Brunner, S. Cohen, M. Freeman, K. Ito, E. Hafen, S. Hayashi, Y. Hiromi, K. Kimura, Y. Nishida, N. Perrimon, G. M. Rubin, L. Raftery, H. Okano, G. Pflugfelder, and the Bloomington Stock Center for fly stocks.

This work was supported by grants-in-aids for scientific research from the Ministry of Education, Science, and Culture of Japan and the Research for the Future program of the Japan Society for the Promotion of Science. M.S. was supported by PHS grant GM47462 to M.B.O. M.C.D. is a Research Associate of the Howard Hughes Medical Institute. M.B.O. is an Associate Investigator of the Howard Hughes Medical Institute.