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A Novel Mechanism of Nuclear Factor B Activation through the Binding between Inhibitor of Nuclear Factor-B and the Processed NH₂-terminal Region of Mig-6¹

Department of Pathology [T. T., J. I., I. B., S. S.] and Director-General [T. S.], Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan; and Department of Urology, Graduate School of Medical Sciences, Kyushu University [T. T., J. I., K. O., S. N.], Fukuoka 812-8582, Japan

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 NH₂-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 (Mig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of B (NFB), which is inhibited by inhibitor of B (IB), and that the processed NH₂-terminal region of Mig-6 but not the full length is bound with IB through its NFB binding region. These findings suggest that the processed CRIB domain of Mig-6 will compete with NFB for IB and result in NFB activation. This novel NFB activation pathway provides new insights regarding tumorigenesis, and the specific inhibition of the cleavage of Mig-6 may be a target for clinical treatment.

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