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 M. Naik, Huaxiu Sui, Wei Tang, Chenxi Qiu, Kazuhiro Koikawa, Felipe Batalini, Emily Stern Gatof, Daniela Arango Isaza, Jaymin M. Patel, Xiaodong Wang, John G. Clohessy, Yujing J. Heng, Galit Lahav, Yansheng Liu, Nathanael S. Gray, Xiao Zhen Zhou (), Wenyi Wei (), Gerburg M. Wulf () and Kun Ping Lu ()
Additional contact information
Shizhong Ke: Harvard Medical School
Fabin Dang: Harvard Medical School
Lin Wang: Harvard Medical School
Jia-Yun Chen: Harvard Medical School
Mandar T. Naik: Brown University
Wenxue Li: Yale Cancer Biology Institute
Abhishek Thavamani: Harvard Medical School
Nami Kim: Harvard Medical School
Nandita M. Naik: Brown University
Huaxiu Sui: Fujian Province University, Xiamen Medical College
Wei Tang: R&D, AstraZeneca
Chenxi Qiu: Harvard Medical School
Kazuhiro Koikawa: Harvard Medical School
Felipe Batalini: Harvard Medical School
Emily Stern Gatof: Harvard Medical School
Daniela Arango Isaza: Harvard Medical School
Jaymin M. Patel: Harvard Medical School
Xiaodong Wang: Harvard T.H. Chan School of Public Health
John G. Clohessy: Harvard Medical School
Yujing J. Heng: Harvard Medical School
Galit Lahav: Harvard Medical School
Yansheng Liu: Yale Cancer Biology Institute
Nathanael S. Gray: Stanford University
Xiao Zhen Zhou: Schulich School of Medicine and Dentistry, Western University
Wenyi Wei: Harvard Medical School
Gerburg M. Wulf: Harvard Medical School
Kun Ping Lu: Schulich School of Medicine and Dentistry, Western University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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. 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/CCDH1 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/CCDH1 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.

Date: 2024
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DOI: 10.1038/s41467-024-47427-w

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