Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56
File(s)Structure EMBO Reports 161016 resubmisiion.pdf (7.52 MB)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2017-03-01
Date Acceptance
2017-01-09
ISSN
1469-221X
Publisher
WILEY
Start Page
437
End Page
450
Journal / Book Title
EMBO REPORTS
Volume
18
Issue
3
Copyright Statement
© 2017 The Author(s). This is the accepted version of the article, which has been published in final form in EMBO reports (2017) 18, 437-450, https://dx.doi.org/10.15252/embr.201642788
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000395061000013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
KIAA1524
phosphorylation
PPP2R5A
PPP2R5C
RAS
PROTEIN PHOSPHATASE 2A
BREAST-CANCER CELLS
C-MYC
REGULATORY SUBUNITS
TRANSFORMATION
TARGET
DEGRADATION
THERAPY
IDENTIFICATION
Autoantigens
Binding Sites
Humans
Membrane Proteins
Models, Molecular
Mutation
Oncogene Proteins
Protein Binding
Protein Conformation
Protein Interaction Mapping
Protein Multimerization
Protein Phosphatase 2
Protein Stability
Protein Subunits
Structure-Activity Relationship
Tumor Suppressor Proteins
0601 Biochemistry And Cell Biology
Developmental Biology
Publication Status
Published
Date Publish Online
2017-02-07