Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase

Cyclin E binds and activates the cyclin-dependent kinase Cdk2 and catalyzes the transition from the G(1) phase to the S phase of the cell cycle. The a mount of cyclin E protein present in the cell is tightly controlled by ubiq uitin-mediated proteolysis. Here we identify the ubiquitin ligase responsib le for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functi onally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCF Fbw7 catalyzes cyclin E ubiquitinati on in vitro. Depletion of Fbw7 leads to accumulation and stabilization of c yclin E in vivo in human and Drosophila melanogaster cells. Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap i n SCF E3 ligase specificity that allows combinatorial control of cyclin E d egradation.