Updated project metadata. Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Notably, Proline-directed phosphorylation is regulated by PIN1-catalyzed cis-trans prolyl isomerization to drive tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell cycle entry.