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 JanssensAlexander Leitner, Jukka Westermarck

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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.

Original languageEnglish
Article number1143
JournalNature Communications
Issue number1
Publication statusPublished - 2023
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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