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Molecular and Cellular Biology, February 2001, p. 1024-1035, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1024-1035.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Shared Pathways of Ikappa B Kinase-Induced SCFbeta TrCP-Mediated Ubiquitination and Degradation for the NF-kappa B Precursor p105 and Ikappa Balpha

Vigo Heissmeyer, Daniel Krappmann, Eunice N. Hatada,dagger and Claus Scheidereit*

Max-Delbrück-Center for Molecular Medicine, 13122 Berlin, Germany

Received 2 August 2000/Returned for modification 26 September 2000/Accepted 15 November 2000

p105 (NFKB1) acts in a dual way as a cytoplasmic Ikappa B molecule and as the source of the NF-kappa B p50 subunit upon processing. p105 can form various heterodimers with other NF-kappa B subunits, including its own processing product, p50, and these complexes are signal responsive. Signaling through the Ikappa B kinase (IKK) complex invokes p105 degradation and p50 homodimer formation, involving p105 phosphorylation at a C-terminal destruction box. We show here that IKKbeta phosphorylation of p105 is direct and does not require kinases downstream of IKK. p105 contains an IKK docking site located in a death domain, which is separate from the substrate site. The substrate residues were identified as serines 923 and 927, the latter of which was previously assumed to be a threonine. S927 is part of a conserved DSGPsi motif and is functionally most critical. The region containing both serines is homologous to the N-terminal destruction box of Ikappa Balpha , -beta , and -varepsilon . Upon phosphorylation by IKK, p105 attracts the SCF E3 ubiquitin ligase substrate recognition molecules beta TrCP1 and beta TrCP2, resulting in polyubiquitination and complete degradation by the proteasome. However, processing of p105 is independent of IKK signaling. In line with this and as a physiologically relevant model, lipopolysaccharide (LPS) induced degradation of endogenous p105 and p50 homodimer formation, but not processing in pre-B cells. In mutant pre-B cells lacking IKKgamma , processing was unaffected, but LPS-induced p105 degradation was abolished. Thus, a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.

* Corresponding author. Mailing address: Max-Delbrück-Center for Molecular Medicine, Cell Growth and Differentiation Program, Robert-Rössle-Str. 10, 13122 Berlin, Germany. Phone: 49-30-9406-3816. Fax: 49-30-9406-3866. E-mail: scheidereit{at}mdc-berlin.de.

dagger Present address: Department of Pathology, Cornell University Medical College, New York, NY 10021.

Molecular and Cellular Biology, February 2001, p. 1024-1035, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1024-1035.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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