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PXD026666 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCell killing by iHAP and DT-061 is not through PP2A-B56 activation
DescriptionPP2A 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.
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterMark Adamo
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListCarbamidomethyl; Oxidation
InstrumentOrbitrap Fusion Lumos; Q Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-06-11 14:26:12ID requested
12022-05-13 07:51:29announced
Publication List
no publication
Keyword List
submitter keyword: PP2A, phosphatase, tumor, kinase, holoenzyme, DT-061, iHAP, PP2A-B56, B56, cell killing, golgi, phenothiazine
Contact List
Arminja Kettenbach
contact affiliationThe Geisel School of Medicine at Dartmouth
contact emailarminja.n.kettenbach@dartmouth.edu
lab head
Mark Adamo
contact affiliationDartmouth College
contact emailmark.e.adamo@dartmouth.edu
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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