Reciprocal antagonism of PIN1-APC/C CDH1 governs mitotic protein stability and cell cycle entry

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/C ) 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 kn...

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Published in:Nature communications 2024-04, Vol.15 (1), p.3220
Main Authors: Ke, Shizhong, Dang, Fabin, Wang, Lin, Chen, Jia-Yun, Naik, Mandar T, Li, Wenxue, Thavamani, Abhishek, Kim, Nami, Naik, Nandita M, Sui, Huaxiu, Tang, Wei, Qiu, Chenxi, Koikawa, Kazuhiro, Batalini, Felipe, Stern Gatof, Emily, Isaza, Daniela Arango, Patel, Jaymin M, Wang, Xiaodong, Clohessy, John G, Heng, Yujing J, Lahav, Galit, Liu, Yansheng, Gray, Nathanael S, Zhou, Xiao Zhen, Wei, Wenyi, Wulf, Gerburg M, Lu, Kun Ping
Format: Article
Language:English
Subjects:
Anaphase-Promoting Complex-Cyclosome - metabolism
Cell Cycle - physiology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Mitosis
NIMA-Interacting Peptidylprolyl Isomerase - genetics
NIMA-Interacting Peptidylprolyl Isomerase - metabolism
Phosphorylation
Protein Stability
Proteomics
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Summary:Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/C ) 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 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 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 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.
ISSN:2041-1723