Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry
Shizhong Ke, Fabin Dang, Lin Wang, Jia-Yun Chen, Mandar T. Naik, Wenxue Li, Abhishek Thavamani, Nami Kim, Nandita Naik, Huaxiu Sui, Wei Tang, Chenxi Qiu, Kazuhiro Koikawa, Felipe Batalini, Emily Stern Gatof, Daniela Arango Isaza, Jaymin Patel, Xiaodong Wang, John G. Clohessy, Yujing J. Heng, Galit Lahav, Yansheng Liu, Nathanael S. Gray, Xiao Zhen Zhou, Wenyi Wei, Gerburg M. Wulf, Kun Ping Lu
Abstract
Abstract Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/C CDH1 ) 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/C CDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/C CDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/C CDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.