Proteomics

Dataset Information

0

Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A


ABSTRACT: Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 trimer, CIP2A replaces PP2A-A subunit and thereby hijacks both the B56 and the catalytic PP2Ac subunit to form a CIP2A-B56-PP2Ac pseudotrimer. Further, CIP2A competes with B56 substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumor growth. Collectively, we discover a unique multi-step “hijack and mute” mechanism of protein complex regulation inhibiting tumor suppressor PP2A-B56. Further, the results unfold single structural determinant for CIP2A´s oncogenic activity, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Rita Derua  

LAB HEAD: Jukka Westermarck

PROVIDER: PXD030297 | Pride | 2023-03-11

REPOSITORIES: Pride

altmetric image

Publications


The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes wi  ...[more]

Similar Datasets

2014-05-28 | E-GEOD-58008 | biostudies-arrayexpress
2020-05-26 | PXD010612 | Pride
2015-08-24 | PXD001374 | Pride
2021-09-08 | PXD008983 | Pride
2018-10-11 | PXD009900 | Pride
2023-02-06 | GSE224212 | GEO
2019-05-16 | MSV000083785 | MassIVE
2019-08-28 | MSV000084245 | MassIVE
2022-05-16 | PXD019647 | Pride
2022-10-21 | PXD035179 | Pride