Abstract
In many physiological and disease processes, TGF-beta usurps branches of MAP kinase pathways in conjunction with Smads to induce apoptosis and epithelial-to-mesenchymal transition, but the detailed mechanism of how a MAP kinase cascade is activated by TGF-beta receptors is not clear. We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38, and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors. TGF-beta induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1. Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1beta/Toll-like receptor pathway.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line
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Enzyme Activation / drug effects
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Epithelium / drug effects
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Epithelium / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Lysine / metabolism
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MAP Kinase Kinase Kinases / metabolism
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Mesoderm / drug effects
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Mesoderm / metabolism
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Mice
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Protein Binding / drug effects
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects
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Smad Proteins / metabolism
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TNF Receptor-Associated Factor 6 / metabolism*
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Transforming Growth Factor beta / pharmacology*
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Ubiquitination / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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TNF Receptor-Associated Factor 6
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Transforming Growth Factor beta
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Lysine