Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56.
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.
Department of Biological Structure, University of Washington, Seattle, WA, USA.|College of Life Sciences, Nankai University, Tianjin, China.
Jiao
J
Wang
Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Åbo Akademi University, Turku, Finland.
Juha
J
Okkeri
Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Åbo Akademi University, Turku, Finland.
Karolina
K
Pavic
Department of Biological Structure, University of Washington, Seattle, WA, USA.
Zhizhi
Z
Wang
Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.
Otto
O
Kauko
Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Åbo Akademi University, Turku, Finland.
Tuuli
T
Halonen
Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
Grzegorz
G
Sarek
Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
Päivi M
PM
Ojala
College of Life Sciences, Nankai University, Tianjin, China.
Zihe
Z
Rao
Department of Biological Structure, University of Washington, Seattle, WA, USA wxu@u.washington.edu jukwes@utu.fi.
Wenqing
W
Xu
Turku Centre for Biotechnology, University of Turku, Turku, Finland wxu@u.washington.edu jukwes@utu.fi.|Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.
Jukka
0000-0001-7478-3018
J
Westermarck
D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D021122:Protein Subunits; D025521:Tumor Suppressor Proteins; C572369:PP2A-B56alpha protein, human; D054648:Protein Phosphatase 2

RAS
; KIAA1524; PPP2R5A; PPP2R5C; phosphorylation