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; Kun Ping Lu

doi:10.1038/s41467-024-47427-w

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

Nat Commun. 2024 Apr 15;15(1):3220. doi: 10.1038/s41467-024-47427-w.

Authors

Shizhong Ke^#¹, Fabin Dang^#², Lin Wang^#¹, Jia-Yun Chen^#^{3

4}, Mandar T Naik⁵, Wenxue Li⁶, Abhishek Thavamani¹, Nami Kim¹, Nandita M Naik⁵, Huaxiu Sui⁷, Wei Tang⁸, Chenxi Qiu^{1

9}, Kazuhiro Koikawa¹, Felipe Batalini^{1

10}, Emily Stern Gatof¹, Daniela Arango Isaza¹, Jaymin M Patel¹, Xiaodong Wang¹¹, John G Clohessy¹², Yujing J Heng², Galit Lahav³, Yansheng Liu^{6

13}, Nathanael S Gray¹⁴, Xiao Zhen Zhou¹⁵, Wenyi Wei¹⁶, Gerburg M Wulf¹⁷, Kun Ping Lu¹⁸

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
² Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA.
³ Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
⁴ Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02215, USA.
⁵ Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912, USA.
⁶ Yale Cancer Biology Institute, West Haven, CT, 06516, USA.
⁷ Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, China.
⁸ Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, MD, USA.
⁹ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
¹⁰ Department of Medicine, Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.
¹¹ Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02215, USA.
¹² Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
¹³ Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06510, USA.
¹⁴ Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.
¹⁵ Departments of Pathology and Laboratory Medicine, Biochemistry, and Oncology, and Lawson Health Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. [email protected].
¹⁶ Department of Pathology, Beth Israel Deaconess Medical Center and Cancer Research Institute, Harvard Medical School, Boston, MA, 02215, USA. [email protected].
¹⁷ Division of Hematology/Oncology, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. [email protected].
¹⁸ Departments of Biochemistry and Oncology, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 3K7, Canada. [email protected].

^# Contributed equally.

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.

MeSH terms

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*

Substances

Anaphase-Promoting Complex-Cyclosome
Cell Cycle Proteins
NIMA-Interacting Peptidylprolyl Isomerase

Abstract

MeSH terms

Substances

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