PXD026666

PXD026666 is an original dataset announced via ProteomeXchange.

Dataset Summary

Title	Cell killing by iHAP and DT-061 is not through PP2A-B56 activation
Description	PP2A is an abundant ser/thr protein phosphatase that act as a tumor suppressor by antagonizing multiple oncogenic kinases. For this reason, compounds able to activate PP2A holoenzymes are attractive anticancer agents. DT-061 and iHAP are phenothiazine derivatives that have recently been claimed to activate specific PP2A-B56 complexes to mediate cell killing. Here we show that iHAP and DT-061 do not activate PP2A-B56 complexes in vitro and that CRISPR removal of B56 regulatory subunits does not affect cellular toxicity of the compounds. Through genome-wide CRISPR screens we uncover the cell killing mechanism of iHAP and DT-061. We find that iHAP is a microtubule poison and removal of mitotic regulators causes hypersensitivity. In contrast, DT-061 disrupts both Golgi and ER consistent with an impact on cellular lipid composition. Indeed, we directly visualize DT-061 in cytoplasmic granules that co-localize with Golgi markers shortly after addition of the compound. Our work uncovers that well known side-effects of phenothiazine derived compounds cause cell killing by iHAP and DT-061 arguing that these compounds cannot be used for dissecting PP2A biology.
HostingRepository	MassIVE
AnnounceDate	2022-05-13
AnnouncementXML	Submission_2022-05-13_07:51:29.182.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Mark Adamo
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Carbamidomethyl; Oxidation
Instrument	Orbitrap Fusion Lumos; Q Exactive Plus

Dataset History

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-11 14:26:12	ID requested
⏵ 1	2022-05-13 07:51:29	announced

Publication List

no publication

no publication

Keyword List

submitter keyword: PP2A, phosphatase, tumor, kinase, holoenzyme, DT-061, iHAP, PP2A-B56, B56, cell killing, golgi, phenothiazine

submitter keyword: PP2A, phosphatase, tumor, kinase, holoenzyme, DT-061, iHAP, PP2A-B56, B56, cell killing, golgi, phenothiazine

Contact List

Arminja Kettenbach
contact affiliation	The Geisel School of Medicine at Dartmouth
contact email	arminja.n.kettenbach@dartmouth.edu
lab head
Mark Adamo
contact affiliation	Dartmouth College
contact email	mark.e.adamo@dartmouth.edu
dataset submitter

Full Dataset Link List

MassIVE dataset URI
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://massive.ucsd.edu/MSV000087616/

MassIVE dataset URI

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://massive.ucsd.edu/MSV000087616/