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PXD006139

PXD006139 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCompetitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits Glycogen Synthase Kinase 3 Beta and Activates WNT Signaling
DescriptionThe cellular and organismal phenotypic response to a small molecule kinase inhibitor is defined collectively by the inhibitor’s targets and their functions. The selectively of small molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based approach to define the target landscape of kinase inhibitors. Here we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib, and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3 and GSK3 were the most potently inhibited. Cell based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits (GSK3/β) kinase activity at low nanomolar concentrations. Consequently, abemaciclib activates β-catenin-dependent WNT signaling, as determined by β-catenin transcriptional activation and β-catenin protein stabilization. These data reveal differential kinase target specificities for CDK4/6 inhibitors may help explain differential clinical efficacy and dose-limiting toxicities. More broadly, we highlight the power of competitive chemical proteomics to identify multiple targets of kinase inhibitors in protein lysate, treated cells and in treated mice.
HostingRepositoryPRIDE
AnnounceDate2017-12-07
AnnouncementXMLSubmission_2017-12-07_03:43:49.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterDennis Goldfarb
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos; LTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02017-03-21 04:42:43ID requested
12017-12-07 03:43:50announced
Publication List
Cousins EM, Goldfarb D, Yan F, Roques J, Darr D, Johnson GL, Major MB, and Activates WNT Signaling. Mol Cancer Res, 16(2):333-344(2018) [pubmed]
Keyword List
curator keyword: Biomedical
submitter keyword: Kinase, chemoproteomics, GSK3β, WNT signaling, polypharmacology
Contact List
Ben Major
contact affiliationDepartment of Cell Biology and Physiology Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill 450 West Drive Lineberger Building CB#7295 Chapel Hill, NC, 27599, USA. Telephone: (919)-259-2695.
contact emailben_major@med.unc.edu
lab head
Dennis Goldfarb
contact affiliationCell and Developmental Biology
contact emaildennisg@email.unc.edu
dataset submitter
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Dataset FTP location
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