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

Nat Commun. 2023 Feb 28;14(1):1143. doi: 10.1038/s41467-023-36693-9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids
  • Carcinogenesis* / genetics
  • Carcinogenesis* / metabolism
  • Catalytic Domain
  • Humans
  • Phosphorylation
  • Protein Phosphatase 2* / genetics
  • Protein Phosphatase 2* / ultrastructure
  • Protein Processing, Post-Translational*
  • Triple Negative Breast Neoplasms* / metabolism


  • Amino Acids
  • CIP2A protein, human
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2