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.
Pubmed ID: 11864612 RIS Download
Antigens, CD | Benzoquinones | Carrier Proteins | Cell Cycle Proteins | Chaperonins | Drosophila Proteins | Enzyme Activation | HSP90 Heat-Shock Proteins | HeLa Cells | Humans | I-kappa B Kinase | Interleukin-1 | Lactams, Macrocyclic | Mitogen-Activated Protein Kinases | Molecular Chaperones | Multienzyme Complexes | NF-kappa B | Protein Interaction Mapping | Protein Structure, Tertiary | Protein Transport | Protein-Serine-Threonine Kinases | Quinones | Receptors, Tumor Necrosis Factor | Receptors, Tumor Necrosis Factor, Type I | Recombinant Proteins | Transcription, Genetic | Tumor Necrosis Factor-alpha