TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90

Mol Cell. 2002 Feb;9(2):401-10. doi: 10.1016/s1097-2765(02)00450-1.

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

  • Antigens, CD / drug effects
  • Antigens, CD / metabolism
  • Benzoquinones
  • Carrier Proteins*
  • Cell Cycle Proteins / physiology*
  • Chaperonins
  • Drosophila Proteins*
  • Enzyme Activation / drug effects
  • HSP90 Heat-Shock Proteins / physiology*
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Interleukin-1 / pharmacology
  • Lactams, Macrocyclic
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Chaperones / physiology*
  • Multienzyme Complexes / metabolism*
  • NF-kappa B / metabolism
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Quinones / pharmacology
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins / pharmacology
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antigens, CD
  • Benzoquinones
  • CDC37 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Drosophila Proteins
  • HSP90 Heat-Shock Proteins
  • IKBKG protein, human
  • Interleukin-1
  • Lactams, Macrocyclic
  • Molecular Chaperones
  • Multienzyme Complexes
  • NF-kappa B
  • Quinones
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Mitogen-Activated Protein Kinases
  • Chaperonins
  • geldanamycin