A ubiquitin ligase complex essential for the NF-kappa B, Wnt/Wingless, and Hedgehog signaling pathways

Ubiquitin-dependent proteolysis by the proteasome plays an essential role in a number of key biological processes, including cell cycle progression, transcription, and signal transduction (for review, see Peters et al. 1998). In many cases the target protein is first marked for degradation or processing by phosphorylation. The phosphorylated protein is then recognized and ubiquitinated in a process that requires three proteins (Hershko et al. 1983; for review, see Hershko 1998; Peters et al. 1998). Ubiquitin is first attached to a ubiquitin-activating enzyme (E1) in an ATP-dependent reaction to form a highenergy thiolester bond. The ubiquitin is then transferred from the E1 protein to an E2 ubiquitin-conjugating enzyme, which functions in conjunction with an E3 protein to link ubiquitin to lysine residues in the targeted protein. A specific lysine residue in the conjugated ubiquitin is then attached to a second ubiquitin, and reiteration of this process results in the assembly of a polyubiquitin chain. The polyubiquitinated protein can then be recognized by the 26S proteasome and degraded or processed.