SCF-Mediated Cdh1 Degradation Defines a Negative Feedback System that Coordinates Cell-Cycle Progression

Proper cell-cycle transitions are driven by waves of ubiquitin-dependent degradation of key regulators by the anaphase-promoting complex (APC) and Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase complexes. But precisely how APC and SCF activities are coordinated to regulate cell-cycle progression remains largely unclear. We previously showed that APC/Cdh1 earmarks the SCF component Skp2 for degradation. Here, we continue to report that SCFβ-TRCP reciprocally controls APC/Cdh1 activity by governing Cdh1 ubiquitination and subsequent degradation. Furthermore, we define both cyclin A and Plk1, two well-known Cdh1 substrates, as upstream modifying enzymes that promote Cdh1 phosphorylation to trigger Cdh1 ubiquitination and subsequent degradation by SCFβ-TRCP. Thus, our work reveals a negative repression mechanism for SCF to control APC, thereby illustrating an elegant dual repression system between these two E3 ligase complexes to create the ordered cascade of APC and SCF activities governing timely cell-cycle transitions. [Display omitted] •SCFβ-TRCP promotes ubiquitination and degradation of the cell-cycle regulator Cdh1•Plk1 and Cdk2/cyclin A synergistically promote Cdh1/b-TRCP1 interaction•SCFβ-TRCP governs APC/Cdh1 activity to ensure proper cell-cycle progression•Crosstalk between APC and SCF defines an ordered cascade of APC and SCF activity Proper cell-cycle transitions are driven by waves of degradation of key regulators controlled by the E3 ubiquitin ligase complexes, anaphase-promoting complex (APC) and Skp1-Cullin1-F-box (SCF). Inuzuka, Wei, and colleagues report that SCFβ-TRCP reciprocally controls APC activity by governing the ubiquitination and degradation of Cdh1 (an APC substrate adaptor) in a cyclin-A- and Plk1-dependent manner. This illustrates an elegant dual repression system between these two E3 ligase complexes to create an ordered cascade of APC and SCF activity that governs timely cell-cycle transitions.