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

Author

Listed:
  • Shizhong Ke

    (Harvard Medical School)

  • Fabin Dang

    (Harvard Medical School)

  • Lin Wang

    (Harvard Medical School)

  • Jia-Yun Chen

    (Harvard Medical School
    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
    Harvard Medical School)

  • Kazuhiro Koikawa

    (Harvard Medical School)

  • Felipe Batalini

    (Harvard Medical School
    Mayo Clinic)

  • 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
    Yale University School of Medicine)

  • 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)

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.

Suggested Citation

  • 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 Batal, 2024. "Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47427-w
    DOI: 10.1038/s41467-024-47427-w
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