TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.
TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappaB 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-kappaB and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappaB activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappaB and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.
Shim
Jae-Hyuck
JH
Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Xiao
Changchun
C
Paschal
Amber E
AE
Bailey
Shannon T
ST
Rao
Ping
P
Hayden
Matthew S
MS
Lee
Ki-Young
KY
Bussey
Crystal
C
Steckel
Michael
M
Tanaka
Nobuyuki
N
Yamada
Gen
G
Akira
Shizuo
S
Matsumoto
Kunihiro
K
Ghosh
Sankar
S
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D020690:GTPase-Activating Proteins; D051550:I-kappa B Kinase; D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011494:Protein Kinases; D011971:Receptors, Immunologic; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C490620:Ralbp1 protein, mouse; C099510:TAB1 protein, MAPKKK activator, vertebrate; C507768:IRAK1 protein, human; C507769:Irak1 protein, mouse