PXD014186

PXD014186 is an original dataset announced via ProteomeXchange.

Title	Phenotypic Proteomic Profiling Reveals Convergent Kinase Targets for Circadian Clock Modulators
Description	Determining 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:56:45.205.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sandipan Ray
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-10 01:23:47	ID requested
1	2019-11-25 03:21:16	announced
2	2020-01-14 07:21:08	announced	2020-01-14: Updated publication reference for PubMed record(s): 31792063.
⏵ 3	2024-10-22 04:56:46	announced	2024-10-22: Updated project metadata.

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]

10.26508/lsa.201900603;

submitter keyword: Circadian rhythms

Circadian period altering compounds

Kinase

Phenotypic proteome profiling

Phosphoproteome

Proteomics

Thermal proteome profiling

Akhilesh B. Reddy
contact affiliation	Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
contact email	areddy@cantab.net
lab head
Sandipan Ray
contact affiliation	University of Pennsylvania
contact email	sandipan.ray@cantab.net
dataset submitter

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://ftp.pride.ebi.ac.uk/pride/data/archive/2019/11/PXD014186

PRIDE project URI

• PRIDE
  1. PXD014186
     1. Label: PRIDE project
     2. Name: Phenotypic Proteomic Profiling Reveals Convergent Kinase Targets for Circadian Clock Modulators