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Molecular and Cellular Biology, April 2004, p. 3048-3056, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.3048-3056.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of NF-B Activity by IBß in Association with B-Ras

Yi Chen,^1, Sebastien Vallee,^1, Joann Wu,¹ Don Vu,¹ John Sondek,² and Gourisankar Ghosh^1*

Department of Chemistry and Biochemistry, University of California—San Diego, La Jolla, California 92093,¹ Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599²

Received 3 December 2003/ Accepted 6 January 2004

IBß, one of the major IB proteins, is only partially degraded in response to most extracellular signals. However, the molecular mechanism of this event is unknown. We show here that IBß exists in at least two different forms: one that is bound to the NF-B dimer and the other bound to both NF-B and B-Ras, a Ras-like small G protein. Removal of cellular B-Ras enhances whereas excess B-Ras blocks induced IBß degradation. Remarkably, B-Ras functions in both GDP- and GTP-bound states, and mutations of the conserved guanine-binding residues of B-Ras abrogate its ability to block degradation of IBß. B-Ras also directly blocks the in vitro phosphorylation of IBß by IKKß. These observations suggest that IBß 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 IBß.

Y.C. and S.V. contributed equally to this work.

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