Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56

EMBO Rep. 2017 Mar;18(3):437-450. doi: 10.15252/embr.201642788. Epub 2017 Feb 7.

Abstract

Protein phosphatase 2A (PP2A) is a critical human tumor suppressor. Cancerous inhibitor of PP2A (CIP2A) supports the activity of several critical cancer drivers (Akt, MYC, E2F1) and promotes malignancy in most cancer types via PP2A inhibition. However, the 3D structure of CIP2A has not been solved, and it remains enigmatic how it interacts with PP2A. Here, we show by yeast two-hybrid assays, and subsequent validation experiments, that CIP2A forms homodimers. The homodimerization of CIP2A is confirmed by solving the crystal structure of an N-terminal CIP2A fragment (amino acids 1-560) at 3.0 Å resolution, and by subsequent structure-based mutational analyses of the dimerization interface. We further describe that the CIP2A dimer interacts with the PP2A subunits B56α and B56γ. CIP2A binds to the B56 proteins via a conserved N-terminal region, and dimerization promotes B56 binding. Intriguingly, inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A, indicating opportunities for controlled degradation. These results provide the first structure-function analysis of the interaction of CIP2A with PP2A/B56 and have direct implications for its targeting in cancer therapy.

Keywords: RAS; KIAA1524; PPP2R5A; PPP2R5C; phosphorylation.

MeSH terms

  • Autoantigens / chemistry
  • Autoantigens / metabolism*
  • Binding Sites
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Mutation
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping
  • Protein Multimerization
  • Protein Phosphatase 2 / chemistry
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Protein Stability
  • Protein Subunits / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Autoantigens
  • CIP2A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oncogene Proteins
  • Protein Subunits
  • Tumor Suppressor Proteins
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2