TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90.
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.
Chen
Guoqing
G
Tularik, Incorporated, Two Corporate Drive, South San Francisco, CA 94080, USA.
Cao
Ping
P
Goeddel
David V
DV
D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D016227:Benzoquinones; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D018833:Chaperonins; D029721:Drosophila Proteins; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones / Q000502:physiology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011809:Quinones / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D016227:Benzoquinones; C498362:CDC37 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; C491731:IKBKG protein, human; D007375:Interleukin-1; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011809:Quinones; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020928:Mitogen-Activated Protein Kinases; D018833:Chaperonins; C001277:geldanamycin