IKAP is a scaffold protein of the IkappaB kinase complex.
The transcription factor NF-kappaB coordinates the activation of numerous genes in response to pathogens and pro-inflammatory cytokines, and is, therefore, vital in the development of acute and chronic inflammatory diseases. NF-kappaB is activated by phsophorylation of its inhibitory subunit, IkappaB-alpha, on serine residues 32 and 36 by cytokine-activated IKB kinases (IKKs); this phosphorylation precedes rapid degradation of IkappaB. IKK-alpha and IKK-beta isozymes are found in large complexes of relative molecular mass 700,000-900,000 (M(r) 70K-90K), but little is known about other components that organize and regulate these complexes. IKK-alpha was independently discovered as a NF-kappaB-inducing kinase (NIK)-associated protein in a yeast two-hybrid screen, and IKK-beta was also identified by homology screening. It is, however, unknown whether NIK is part of the IKK complex. Here we isolate large, interleukin-1-inducible IKK complexes that contain NIK, IKK-alpha, IKK-beta, IkappaB-alpha, NF-kappaB/RelA and a protein of M(r) 150K. This latter component is a new protein, termed IKK-complex-associated protein (IKAP), which can bind NIK and IKKs and assemble them into an active kinase complex. We show that IKAP is a scaffold protein and a regulator for three different kinases involved in pro-inflammatory cytokine signalling.
Cohen
L
L
Tularik Inc., South San Francisco, California 94080, USA.
Henzel
W J
WJ
Baeuerle
P A
PA
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004790:Enzyme Induction; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D015530:Nuclear Matrix / Q000201:enzymology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D035602:Transcriptional Elongation Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002352:Carrier Proteins; C114720:Elp1 protein, human; D007375:Interleukin-1; D035602:Transcriptional Elongation Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase