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

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 Honkanen, Daniel Abankwa, Maja Köhn, Vesa P. Hytönen, Wenqing Xu, Jakob Nilsson, Rebecca Page, Veerle Janssens, Alexander Leitner and Jukka Westermarck ()
Additional contact information
Karolina Pavic: University of Turku and Åbo Akademi University
Nikhil Gupta: University of Turku and Åbo Akademi University
Judit Domènech Omella: University of Leuven (KU Leuven)
Rita Derua: 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
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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36693-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36693-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36693-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().