PXD030297-1

PXD030297 is an original dataset announced via ProteomeXchange.

Title	Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A
Description	Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition 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.
HostingRepository	PRIDE
AnnounceDate	2023-03-11
AnnouncementXML	Submission_2023-03-11_00:28:08.679.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030297
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	RitaDerua
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-10 02:42:06	ID requested
⏵ 1	2023-03-11 00:28:09	announced
2	2023-11-14 08:39:27	announced	2023-11-14: Updated project metadata.

10.6019/PXD030297;

Pavic K, Gupta N, Omella JD, Derua R, Aakula A, Huhtaniemi R, M, ä, ä, tt, ä JA, H, ö, fflin N, Okkeri J, Wang Z, Kauko O, Varjus R, Honkanen H, Abankwa D, K, ö, hn M, Hyt, ö, nen VP, Xu W, Nilsson J, Page R, Janssens V, Leitner A, Westermarck J, and oncogenicity by CIP2A. Nat Commun, 14(1):1143(2023) [pubmed]

submitter keyword: AP-MS, protein phosphatase,Mouse, oncogene, interactome

JukkaWestermarck
contact affiliation	Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland Institute of Biomedicine, University of Turku, 20520 Turku, Finland
contact email	jukka.westermarck@utu.fi
lab head
RitaDerua
contact affiliation	KU Leuven
contact email	rita.derua@kuleuven.be
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD030297

PRIDE project URI

• PRIDE
  1. PXD030297
     1. Label: PRIDE project
     2. Name: Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A