Abstract
The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB. We identify Cdc37 and Hsp90 as two additional components of the IKK complex. IKKalpha/IKKbeta/NEMO and Cdc37/Hsp90 form an approximately 900 kDa heterocomplex, which is assembled via direct interactions of Cdc37 with Hsp90 and with the kinase domain of IKKalpha/IKKbeta. Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB. GA treatment reduces the size of the IKK complex and abolishes TNF-dependent recruitment of the IKK complex to TNF receptor 1 (TNF-R1). Therefore, heterocomplex formation with Cdc37/Hsp90 is a prerequisite for TNF-induced activation and trafficking of IKK from the cytoplasm to the membrane.
MeSH terms
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Antigens, CD / drug effects
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Antigens, CD / metabolism
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Benzoquinones
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Carrier Proteins*
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Cell Cycle Proteins / physiology*
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Chaperonins
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Drosophila Proteins*
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Enzyme Activation / drug effects
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HSP90 Heat-Shock Proteins / physiology*
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HeLa Cells
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Humans
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I-kappa B Kinase
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Interleukin-1 / pharmacology
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Lactams, Macrocyclic
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Chaperones / physiology*
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Multienzyme Complexes / metabolism*
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NF-kappa B / metabolism
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Protein Interaction Mapping
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Protein Transport
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Quinones / pharmacology
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Receptors, Tumor Necrosis Factor / drug effects
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins / pharmacology
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Antigens, CD
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Benzoquinones
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CDC37 protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Drosophila Proteins
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HSP90 Heat-Shock Proteins
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IKBKG protein, human
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Interleukin-1
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Lactams, Macrocyclic
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Molecular Chaperones
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Multienzyme Complexes
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NF-kappa B
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Quinones
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Mitogen-Activated Protein Kinases
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Chaperonins
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geldanamycin