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

Jiao Wang1,2, Juha Okkeri3,4, Karolina Pavic3,4

  • 1Department of Biological Structure, University of Washington, Seattle, WA, USA.

EMBO Reports
|February 9, 2017
PubMed

Insights

Cancerous inhibitor of protein phosphatase 2A (CIP2A) forms homodimers, enabling interaction with PP2A subunits. This structural insight reveals new therapeutic strategies for targeting CIP2A in cancer.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Protein phosphatase 2A (PP2A) is a crucial human tumor suppressor.
  • Cancerous inhibitor of PP2A (CIP2A) promotes cancer by inhibiting PP2A and activating oncogenic pathways.
  • The structural basis of CIP2A-PP2A interaction remained unknown.

Purpose of the Study:

  • To elucidate the 3D structure of CIP2A and its interaction mechanism with PP2A.
  • To investigate the role of CIP2A homodimerization in its function.
  • To identify potential therapeutic targets for CIP2A in cancer treatment.

Main Methods:

  • Yeast two-hybrid assays for interaction studies.
  • X-ray crystallography to determine the structure of a CIP2A fragment.
  • Structure-based mutational analysis to probe the dimerization interface.
  • Expression analysis of PP2A subunits B56α and B56γ.

Main Results:

  • CIP2A forms homodimers, confirmed by structural and mutational analyses.
  • The crystal structure of the N-terminal CIP2A fragment (1-560) was solved at 3.0 Å resolution.
  • CIP2A dimer binds to PP2A subunits B56α and B56γ via a conserved N-terminal region.
  • Dimerization enhances CIP2A binding to B56 proteins.
  • Inhibition of CIP2A dimerization or B56α/γ expression leads to CIP2A destabilization and degradation.

Conclusions:

  • This study provides the first structure-function analysis of CIP2A interaction with PP2A/B56.
  • CIP2A homodimerization is critical for its binding to PP2A and oncogenic function.
  • Targeting CIP2A dimerization or B56 expression offers novel therapeutic avenues for cancer treatment.
Keywords:
RASKIAA1524PPP2R5APPP2R5Cphosphorylation

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