A novel mechanism of nuclear factor kappaB activation through the binding between inhibitor of nuclear factor-kappaBalpha and the processed NH(2)-terminal region of Mig-6.
Mitogene-inducible gene-6 (Mig-6), an adaptor molecule containing the Cdc42/Rac interaction and binding (CRIB) domain, is rapidly induced by mitogenic and stressful stimuli, and sustained mig-6 expression is observed in chronic pathological conditions. The function of this molecule has remained elusive. We find that mig-6 is constitutively expressed in many human cancer cell lines, and Mig-6 is cleaved into the NH(2)-terminal region containing the CRIB domain and the remainder of the COOH-terminal region by limited proteolytic processing. We report here that full-length Mig-6, but not CRIB domain-deleted Mig-6 (DeltaMig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of kappaB (NFkappaB), which is inhibited by inhibitor of kappaBalpha (IkappaBalpha), and that the processed NH(2)-terminal region of Mig-6 but not the full length is bound with IkappaBalpha through its NFkappaB binding region. These findings suggest that the processed CRIB domain of Mig-6 will compete with NFkappaB for IkappaBalpha and result in NFkappaB activation. This novel NFkappaB activation pathway provides new insights regarding tumorigenesis, and the specific inhibition of the cleavage of Mig-6 may be a target for clinical treatment.
Tsunoda
Toshiyuki
T
Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan.
Inokuchi
Junichi
J
Baba
Iwai
I
Okumura
Koji
K
Naito
Seiji
S
Sasazuki
Takehiko
T
Shirasawa
Senji
S
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D011233:Precipitin Tests; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C484017:ERRFI1 protein, human; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha