Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry

• Published in: Nature communications Vol. 15; no. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 13/106; 13/51; 13/89; 13/95; 14; 14/19; 59; 631/337/458/1733; 631/67/1059/602; 631/80/641/2350; Adenomatous polyposis coli; Anaphase; Anaphase-promoting complex; Antagonism; Biodegradation; Cancer; Cancer therapies; Cell cycle; Control theory; Degradation; E-cadherin; Feedback loops; Humanities and Social Sciences; Isomerization; Kinases; Malignancy; multidisciplinary; Peptidylprolyl isomerase; Phosphorylation; Pin1 protein; Positive feedback; Protein turnover; Proteins; Proteomics; Science; Science (multidisciplinary); Stability; Tumors; Ubiquitin-protein ligase
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47427-w

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.
Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/C
CDH1
controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.