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Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A

Author

Listed:
  • Karolina Pavic

    (University of Turku and Åbo Akademi University
    University of Luxembourg)

  • Nikhil Gupta

    (University of Turku and Åbo Akademi University)

  • Judit Domènech Omella

    (University of Leuven (KU Leuven))

  • Rita Derua

    (University of Leuven (KU Leuven)
    University of Leuven (KU Leuven))

  • Anna Aakula

    (University of Turku and Åbo Akademi University)

  • Riikka Huhtaniemi

    (University of Turku and Åbo Akademi University)

  • Juha A. Määttä

    (Tampere University, 33520 Tampere, Finland and Fimlab Laboratories)

  • Nico Höfflin

    (University of Freiburg)

  • Juha Okkeri

    (University of Turku and Åbo Akademi University)

  • Zhizhi Wang

    (ShanghaiTech University)

  • Otto Kauko

    (University of Turku and Åbo Akademi University)

  • Roosa Varjus

    (University of Turku and Åbo Akademi University)

  • Henrik Honkanen

    (University of Turku and Åbo Akademi University)

  • Daniel Abankwa

    (University of Luxembourg)

  • Maja Köhn

    (University of Freiburg
    University of Freiburg)

  • Vesa P. Hytönen

    (Tampere University, 33520 Tampere, Finland and Fimlab Laboratories)

  • Wenqing Xu

    (ShanghaiTech University)

  • Jakob Nilsson

    (University of Copenhagen, Blegdamsvej 3B)

  • Rebecca Page

    (Department of Chemistry and Biochemistry University of Arizona)

  • Veerle Janssens

    (University of Leuven (KU Leuven))

  • Alexander Leitner

    (ETH Zurich)

  • Jukka Westermarck

    (University of Turku and Åbo Akademi University
    University of Turku)

Abstract

The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

Suggested Citation

  • Karolina Pavic & Nikhil Gupta & Judit Domènech Omella & Rita Derua & Anna Aakula & Riikka Huhtaniemi & Juha A. Määttä & Nico Höfflin & Juha Okkeri & Zhizhi Wang & Otto Kauko & Roosa Varjus & Henrik Ho, 2023. "Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36693-9
    DOI: 10.1038/s41467-023-36693-9
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    References listed on IDEAS

    as
    1. Uhn Soo Cho & Wenqing Xu, 2007. "Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme," Nature, Nature, vol. 445(7123), pages 53-57, January.
    2. Cheng-Guo Wu & Aiping Zheng & Li Jiang & Michael Rowse & Vitali Stanevich & Hui Chen & Yitong Li & Kenneth A. Satyshur & Benjamin Johnson & Ting-Jia Gu & Zuojia Liu & Yongna Xing, 2017. "Methylation-regulated decommissioning of multimeric PP2A complexes," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
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