Figure 3.

Function and regulation of the APC/C E3 ligase during somatic cell cycle. At the G1-S transition, accumulated cyclin A and B dependent on the inhibition of APC/C^Cdc20 by APC/C^Cdh1 will activate CDKs and promote entry into S phase. In coordination with increased expression of Emi1 regulated by E2F and Evi5, activated CDKs phosphorylate Cdh1, inhibit APC/C^Cdh1, and cause subsequent accumulation of Plk1. During prometaphase and metaphase, APC/C^Cdc20 is activated by combinatorial factors including downregulation of APC/C^Cdh1, CDK1-dependent APC/C^Cdc20 phosphorylation, dissociation of MCC from APC/C^Cdc20, degradation of Bub1 and Aurora kinases by APC/C^Cdh1 in G1 phase, and proteolysis of Emil by Plk1-dependent phosphorylation. Further enhanced activation of APC/C^Cdc20 can be achieved by degradation of CDK1 inhibitor p21^CIP1 by APC/C^Cdc20. Activated APC/C^Cdc20 initiates the degradation of cyclin A in prometaphase and cyclin B in metaphase and is involved in destruction of securin, which, in turn, reduces CDK1 activity and results in the dephosphorylation of Cdh1, in conjunction with Cdc14 phosphatase dephosphorylation, and activation of APC/C^Cdh1. Dephosphorylation of separase together with the APC/C^Cdh1-dependent proteolysis of securin (Pds1/Cut2) results in the activation of separase, cleavage of cohesin, and anaphase onset. Activated APC/C^Cdh1 orchestrates the degradation of a wide spectrum of substrates, facilitating mitotic exit and cytokinesis.