Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 1143 |
| Tidsskrift | Nature Communications |
| Vol/bind | 14 |
| Antal sider | 18 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Authors acknowledge the Turku Proteomics Facility, Cell Imaging and Cytometry, and Genome Editing Core at Turku Bioscience Centre, and Turku Centre for Disease Modelling at the University of Turku; all supported by Biocenter Finland. Taina Kalevo-Mattila is acknowledged for excellent technical support, as well as the entire Turku Bioscience personnel for excellent working environment. AL would like to thank Ruedi Aebersold (ETH Zurich) for access to infrastructure and instrumentation. The use of the facilities and expertize of the Protein Service core facility of the Tampere University and a member of Biocenter Finland, is gratefully acknowledged. The authors further want to thank Saverio Minucci for generously providing PLA reagents, Stephen Dilworth for PP2A antibodies, Wolfgang Peti for insightful structural biology advice, and Kari Kurppa for help with Crispr/Cas9 targeting. The work was supported by funding from Sigrid Juselius Foundation (J.W.), Academy of Finland (331237; J.W.)(331946; V.H.), Jane and Aatos Erkko Foundation (J.W.), Finnish Cancer Associations (J.W.), Finnish Cultural Foundation (K.P.), Albin Johanssons Foundation (K.P.), F.W.O. - Vlaanderen (Research Foundation – Flanders) (G0B0116N, G0B1719N, and 1S77521N) (V.J., J.D.O.), KU Leuven (C24/17/073) (V.J., R.D.), Belgian Foundation against Cancer (FA/2020/1330)(V.J.) and NIH NIGMS (R01GM144483)(RP).
Funding Information:
Authors acknowledge the Turku Proteomics Facility, Cell Imaging and Cytometry, and Genome Editing Core at Turku Bioscience Centre, and Turku Centre for Disease Modelling at the University of Turku; all supported by Biocenter Finland. Taina Kalevo-Mattila is acknowledged for excellent technical support, as well as the entire Turku Bioscience personnel for excellent working environment. AL would like to thank Ruedi Aebersold (ETH Zurich) for access to infrastructure and instrumentation. The use of the facilities and expertize of the Protein Service core facility of the Tampere University and a member of Biocenter Finland, is gratefully acknowledged. The authors further want to thank Saverio Minucci for generously providing PLA reagents, Stephen Dilworth for PP2A antibodies, Wolfgang Peti for insightful structural biology advice, and Kari Kurppa for help with Crispr/Cas9 targeting. The work was supported by funding from Sigrid Juselius Foundation (J.W.), Academy of Finland (331237; J.W.)(331946; V.H.), Jane and Aatos Erkko Foundation (J.W.), Finnish Cancer Associations (J.W.), Finnish Cultural Foundation (K.P.), Albin Johanssons Foundation (K.P.), F.W.O. - Vlaanderen (Research Foundation – Flanders) (G0B0116N, G0B1719N, and 1S77521N) (V.J., J.D.O.), KU Leuven (C24/17/073) (V.J., R.D.), Belgian Foundation against Cancer (FA/2020/1330)(V.J.) and NIH NIGMS (R01GM144483)(RP).
Publisher Copyright:
© 2023, The Author(s).
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