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

Karolina Pavic1,2, Nikhil Gupta1, Judit Domènech Omella3

  • 1Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.

Nature Communications
|February 28, 2023
PubMed

Insights

The oncoprotein CIP2A inhibits the tumor suppressor PP2A-B56α by hijacking its subunits and blocking substrate binding. This mechanism is crucial for cancer development and offers potential therapeutic targets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Protein phosphatase 2A (PP2A) is a crucial tumor suppressor, with the PP2A-B56α heterotrimer playing a key role.
  • The precise molecular mechanisms by which PP2A-B56α is inhibited in cancer remain largely unknown.
  • CIP2A is an oncoprotein implicated in various human cancers.

Purpose of the Study:

  • To elucidate the structural mechanisms by which the oncoprotein CIP2A inhibits the tumor suppressor PP2A-B56α.
  • To understand how CIP2A binding affects the PP2A-B56α complex and its function.
  • To identify potential therapeutic strategies targeting CIP2A in cancer.

Main Methods:

  • * Investigated the direct binding of CIP2A to the PP2A-B56α heterotrimer.
  • * Determined the structural basis of PP2A-B56α inhibition by CIP2A.
  • * Utilized CRISPR/Cas9-mediated mutagenesis to study the functional impact of CIP2A domains.
  • * Assessed the effect of CIP2A inhibition on MYC expression, MEK phosphorylation, and tumor growth in vivo.

Main Results:

  • * CIP2A directly binds to PP2A-B56α, displacing the PP2A-A subunit and forming a CIP2A-B56α-PP2Ac pseudotrimer.
  • * CIP2A inhibits PP2A-B56α by blocking the LxxIxE-motif substrate binding pocket on the B56α subunit.
  • * The N-terminal head domain of CIP2A interacts with B56α, stabilizing CIP2A.
  • * Mutagenesis of the CIP2A head domain reduced MYC expression, MEK phosphorylation, and triple-negative breast cancer tumor growth in vivo.

Conclusions:

  • * CIP2A inhibits the tumor suppressor PP2A-B56α through a unique multi-step mechanism involving complex hijacking and functional inactivation.
  • * The N-terminal head domain of CIP2A is critical for its oncogenic activity and stabilization.
  • * Understanding this inhibition mechanism reveals a structural determinant for CIP2A's oncogenic role, offering potential for therapeutic intervention in cancer.

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