Inhibition of NF-kappaB activity by IkappaBbeta in association with kappaB-Ras.
IkappaBbeta, one of the major IkappaB proteins, is only partially degraded in response to most extracellular signals. However, the molecular mechanism of this event is unknown. We show here that IkappaBbeta exists in at least two different forms: one that is bound to the NF-kappaB dimer and the other bound to both NF-kappaB and kappaB-Ras, a Ras-like small G protein. Removal of cellular kappaB-Ras enhances whereas excess kappaB-Ras blocks induced IkappaBbeta degradation. Remarkably, kappaB-Ras functions in both GDP- and GTP-bound states, and mutations of the conserved guanine-binding residues of kappaB-Ras abrogate its ability to block degradation of IkappaBbeta. kappaB-Ras also directly blocks the in vitro phosphorylation of IkappaBbeta by IKKbeta. These observations suggest that IkappaBbeta in the ternary complex is resistant to degradation by most signals. We suggest that specific signals, in addition to those that activate only IKK, are essential for the complete degradation of IkappaBbeta.
Chen
Yi
Y
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, California 92093, USA.
Vallee
Sebastien
S
Wu
Joann
J
Vu
Don
D
Sondek
John
J
Ghosh
Gourisankar
G
D000818:Animals; D002460:Cell Line; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D046911:Macromolecular Substances; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; D034741:RNA, Small Interfering; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D018631:ras Proteins