TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-kappaB.
Responses to transforming growth factor beta and multiple cytokines involve activation of transforming growth factor beta-activated kinase-1 (TAK1) kinase, which activates kinases IkappaB kinase (IKK) and MKK3/6, leading to the parallel activation of NF-kappaB and p38 MAPK. Activation of TAK1 by autophosphorylation is known to involve three different TAK1-binding proteins ... (TABs). Here we report a protein phosphatase subunit known as type 2A phosphatase-interacting protein (TIP) that also acts as a TAB because it co-precipitates with and directly binds to TAK1, enhances TAK1 autophosphorylation at unique sites, and promotes TAK1 phosphorylation of IKKbeta and signaling to NF-kappaB. Mass spectrometry demonstrated that co-expression of TAB4 protein significantly increased phosphorylation of four sites in TAK1, in a linker region between the kinase and TAB2/3 binding domains, and two sites in TAB1. Recombinant GST-TAB4 bound in an overlay assay directly to inactive TAK1 and activated TAK1 but not TAK1 phosphorylated in the linker sites, suggesting a bind and release mechanism. In kinase assays using TAK1 immune complexes, added GST-TAB4 selectively stimulated IKK phosphorylation. TAB4 co-precipitated polyubiquitinated proteins dependent on a Phe-Pro motif that was required to enhance phosphorylation of TAK1. TAB4 mutated at Phe-Pro dominantly interfered with IL-1beta activation of NF-kappaB involving IKK-dependent but not p38 MAPK-dependent signaling. The results show that TAB4 binds TAK1 and polyubiquitin chains to promote specific sites of phosphorylation in TAK1-TAB1, which activates IKK signaling to NF-kappaB.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Substitution, Humans, I-kappa B Kinase, Interleukin-1beta, MAP Kinase Kinase 3, MAP Kinase Kinase 6, MAP Kinase Kinase Kinases, Mutation, Missense, NF-kappa B, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Signal Transduction, Transforming Growth Factor beta, Ubiquitin, p38 Mitogen-Activated Protein Kinases
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Substitution, Humans, I-kappa B Kinase, Interleukin-1beta, MAP Kinase Kinase 3, MAP Kinase Kinase 6, MAP Kinase Kinase Kinases, Mutation, Missense, NF-kappa B, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Signal Transduction, Transforming Growth Factor beta, Ubiquitin, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: Jul. 11, 2008
PubMed ID: 18456659
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