Auto phosphorylation of TAK1 within the ALPK1:ADP-heptose:p-T9-TIFA:pUb-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 :MAP3K7 complex

Stable Identifier
Reaction [transition]
Homo sapiens
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The TAK1 complex consists of transforming growth factor-beta (TGFB)-activated kinase (TAK1 or MAP3K7), TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher-order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001).
Literature References
PubMed ID Title Journal Year
10838074 Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1

Sugita, T, Sakurai, H, Mizukami, J, Miyoshi, H

FEBS Lett. 2000
11323434 An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK

Ohtomo, T, Suzuki, M, Hisamoto, N, Sugamata, Y, Ono, K, Sato, S, Matsumoto, K, Tsuchiya, M, Ninomiya-Tsuji, J

J. Biol. Chem. 2001
8638164 TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction

Shibuya, H, Shirakabe, K, Ueno, N, Nishida, E, Matsumoto, K, Gotoh, Y, Yamaguchi, K, Irie, K, Tonegawa, A

Science 1996
16186825 Essential function for the kinase TAK1 in innate and adaptive immune responses

Kawai, T, Takeuchi, O, Sanjo, H, Takeda, K, Ninomiya-Tsuji, J, Sato, S, Yamamoto, M, Akira, S, Matsumoto, K

Nat Immunol 2005
16289117 Structural basis for the interaction of TAK1 kinase with its activating protein TAB1

Dunster, NJ, Brown, K, Vial, SC, Dedi, N, Cheetham, GM, Long, JM

J. Mol. Biol. 2005
16260493 TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo

Shim, JH, Steckel, M, Xiao, C, Yamada, G, Ghosh, S, Paschal, AE, Bussey, C, Matsumoto, K, Tanaka, N, Rao, P, Hayden, MS, Akira, S, Bailey, ST, Lee, KY

Genes Dev 2005
10702308 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop

Kishimoto, K, Ninomiya-Tsuji, J, Matsumoto, K

J Biol Chem 2000
Catalyst Activity

MAP kinase kinase kinase kinase activity of ALPK1:ADP-heptose:p-T9-TIFA:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chain [cytosol]

Orthologous Events
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