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PXD014186

PXD014186 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitlePhenotypic Proteomic Profiling Reveals Convergent Kinase Targets for Circadian Clock Modulators
DescriptionDetermining the mechanisms of action of drug molecules that modulate circadian rhythms is critical to develop novel compounds to treat clock disorders. Here we employed Phenotypic Proteomic Profiling (PPP) integrating multipronged proteomics approaches including global proteome, phosphoproteome, kinome mapping, and proteome-wide profiling of thermal stability (TPP) to systematically determine convergent molecular targets of four circadian period lengthening compounds (Longdaysin, Roscovitine, Purvalanol A, and SP600125) in human cells. We demonstrate convergent changes in phosphorylation level and activity of several proteins and kinases involved in vital signaling pathways including MAPK, NGF, BCR, AMPK, and mTOR signaling by the compounds. Kinome profiling using desthiobiotin-ATP enrichment quantitative proteomics and radiometric assays further indicated inhibition of CKId, ERK1/2, CDK2/7, TNIK and STK26 activity as a common mechanism of action for the compounds. Pharmacological or genetic inhibition of several convergent kinases resulted in circadian period lengthening, establishing them as novel bone fide circadian targets. TPP analysis using live cells revealed binding of these drugs to clock regulatory kinases, signaling molecules, and ubiquitination mediator (F-box) proteins. Phenotypic proteomic profiling thus establishes a set of novel circadian clock effectors.
HostingRepositoryPRIDE
AnnounceDate2019-11-25
AnnouncementXMLSubmission_2020-01-14_07:21:07.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSandipan Ray
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos; Orbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02019-06-10 01:23:47ID requested
12019-11-25 03:21:16announced
22020-01-14 07:21:08announced2020-01-14: Updated publication reference for PubMed record(s): 31792063.
Publication List
Ray S, Lach R, Heesom KJ, Valekunja UK, Encheva V, Snijders AP, Reddy AB, Phenotypic proteomic profiling identifies a landscape of targets for circadian clock-modulating compounds. Life Sci Alliance, 2(6):(2019) [pubmed]
Keyword List
submitter keyword: Circadian rhythms
Circadian period altering compounds
Kinase
Phenotypic proteome profiling
Phosphoproteome
Proteomics
Thermal proteome profiling
Contact List
Akhilesh B. Reddy
contact affiliationDepartment of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
contact emailareddy@cantab.net
lab head
Sandipan Ray
contact affiliationUniversity of Pennsylvania
contact emailsandipan.ray@cantab.net
dataset submitter
Full Dataset Link List
Dataset FTP location
PRIDE project URI
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