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PXD006139

DataSet Summary

  • HostingRepository: PRIDE
  • AnnounceDate: 2017-12-07
  • AnnouncementXML: Submission_2017-12-07_03:43:49.xml
  • DigitalObjectIdentifier:
  • ReviewLevel: Peer-reviewed dataset
  • DatasetOrigin: Original data
  • RepositorySupport: Unsupported dataset by repository
  • PrimarySubmitter: Dennis Goldfarb
  • Title: Competitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits Glycogen Synthase Kinase 3 Beta and Activates WNT Signaling
  • Description: The 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.
  • SpeciesList: scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
  • ModificationList: phosphorylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
  • Instrument: Orbitrap Fusion Lumos; LTQ Orbitrap Elite

Dataset History

VersionDatetimeStatusChangeLog Entry
02017-03-21 04:42:43ID requested
12017-12-07 03:43:50announced

Publication List

  1. Cousins EM, Goldfarb D, Yan F, Roques J, Darr DB, Johnson GL, Major MB, Competitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits GSK3β and Activates WNT Signaling. Mol Cancer Res, ():(2017) [pubmed]

Keyword List

  1. curator keyword: Biomedical
  2. submitter keyword: Kinase, chemoproteomics, GSK3β, WNT signaling, polypharmacology

Contact List

    Ben Major
    • contact affiliation: Department 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 email: ben_major@med.unc.edu
    • lab head:
    Dennis Goldfarb
    • contact affiliation: Cell and Developmental Biology
    • contact email: dennisg@email.unc.edu
    • dataset submitter:

Full Dataset Link List

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