TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.
TAK1, a member of the mitogen-activated kinase kinase kinase family, is activated in vivo by various cytokines, including interleukin-1 (IL-1), or when ectopically expressed together with the TAK1-binding protein TAB1. However, this molecular mechanism of activation is not yet understood. We show here that endogenous TAK1 is constitutively associated with TAB1 and phosphorylated following IL-1 stimulation. Furthermore, TAK1 is constitutively phosphorylated when ectopically overexpressed with TAB1. In both cases, dephosphorylation of TAK1 renders it inactive, but it can be reactivated by preincubation with ATP. A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.
Kishimoto
K
K
Department of Molecular Biology, Graduate School of Science, Nagoya University and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya 464-8602, Japan.
Matsumoto
K
K
Ninomiya-Tsuji
J
J
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
D007375:Interleukin-1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7