Structural mechanism for inhibition of PP2A-B56 alpha and oncogenicity by CIP2A

The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 alpha is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56 alpha in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56 alpha inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 alpha trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56 alpha, and the catalytic PP2Ac subunit to form a CIP2A-B56 alpha-PP2Ac pseudotrimer. Further, CIP2A competes with B56 alpha substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56 alpha. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 alpha 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-B56 alpha 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. Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.