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RESEARCH PAPER
1 Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA; 2 Center for Animal Resources and Development, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan; 3 Department of Molecular Biology, Nagoya University and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya, 464-8602, Japan; 4 Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan; 5 Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, Suita, Osaka 565-0871, Japan
TGF-
-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-
B and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-B and AP-1 activation are severely impaired in Tak1m/m cells, but they are normal in Tab1-/- and Tab2-/- cells. In addition, Tak1m/m cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-
and IL-1 signaling pathways, where it functions downstream of RIP1–TRAF2 and MyD88–IRAK1–TRAF6, respectively. However, TAK1 is not required for NF-B activation through the alternative pathway following LT- signaling. In the TGF- signaling pathway, TAK1 deletion leads to impaired NF-B and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF--induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKK and JNK, but not IKK, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.
[Keywords: JNK; NF-B; TAB1; TAB2; TAK1; TGF-]
Received August 2, 2005; revised version accepted September 19, 2005.
Supplemental material is available at http://www.genesdev.org.
E-MAIL Sankar.ghosh{at}yale.edu; FAX (203) 737-1764.
6 Present address: Center for Blood Research, Harvard Medical School, Brookline, MA 02446, USA.
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