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.
CIP2A promotes malignancy by inhibiting the tumor suppressor activity of the protein phosphatase PP2A. This study presents the first crystal structure of CIP2A and characterizes the structural requirements for the binding of CIP2A to the B56 subunits of PP2A.
Cancerous inhibitor of PP2A (CIP2A) is an obligate dimer that directly interacts with the regulatory PP2A subunits B56α and B56γ.
CIP2A binds to B56 proteins via a conserved N‐terminal region, and CIP2A homodimerization promotes B56 binding.
Inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A.
- Received May 27, 2016.
- Revision received December 20, 2016.
- Accepted January 9, 2017.
- © 2017 The Authors
Subscribers, please sign in with your username and password.