Reactome | beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complex

beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complex

Stable Identifier

R-HSA-5607728

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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beta-TRCP ubiquitinates IkB-alpha in p-S32,33-IkB-alpha:NF-kB complex

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Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).

Literature References

PubMed ID	Title	Journal	Year
8550590	Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha Baldi, L, Franzoso, G, Siebenlist, U, Brown, K	J. Biol. Chem.	1996
14514672	Signal-induced ubiquitination of I kappaB Kinase-beta Pennington, KN, Carter, RS, Ballard, DW, Arrate, P, Ungurait, BJ	J. Biol. Chem.	2003
9990853	Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP Jiang, J, Spencer, E, Chen, ZJ	Genes Dev	1999
7479848	Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway Ciechanover, A, Hatzubai, A, Alkalay, I, Yaron, A, Orian, A, Ben-Neriah, Y	Proc Natl Acad Sci U S A	1995