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PXD023913

PXD023913 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleIntegrated proteomics-based physical and functional mapping of AXL kinase signaling pathways and inhibitors define its role in cell migration: ABPP
DescriptionTo better understand the signaling complexity of AXL, a member of the TAM family of receptor tyrosine kinases, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein-complexes using BioID, effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics reveal that AXL inhibition deregulates phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT and migration/invasion of these cells without reducing their viability, while Bemcentinib exerts AXL-independent phenotypic effects. Proteomic characterization of these TKIs reveals that they inhibit diverse targets in addition to AXL, with Bemcentinib having the most off-targets. AXL and EGFR TKI co-treatment did not reverse resistance in cell line models of Erlotinib resistance. However, a unique vulnerability was identified in one persister clone, wherein combination of Bemcentinib and Erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in ~30-40% of NSCLC but rarely in SCLC. NSCLC cells have a wide range of AXL protein expression, with basal activation detected rarely. Overall, we evaluate the mechanisms of action of AXL in lung cancer which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting its signaling network as an anticancer therapy.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:34:51.023.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD023913
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJohn Koomen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListbiotinylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-02-01 01:16:23ID requested
12022-11-28 15:24:17announced
22023-11-14 08:34:51announced2023-11-14: Updated project metadata.
Publication List
10.6019/PXD023913;
Majumder A, Hosseinian S, Stroud M, Adhikari E, Saller JJ, Smith MA, Zhang G, Agarwal S, Creixell M, Meyer BS, Kinose F, Bowers K, Fang B, Stewart PA, Welsh EA, Boyle TA, Meyer AS, Koomen JM, Haura EB, Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration. Mol Cancer Res, 20(4):542-555(2022) [pubmed]
Keyword List
submitter keyword: ABPP,Lung Cancer, Targeted Therapy, AXL Tyrosine Kinase
Contact List
Eric B. Haura, MD
contact affiliationMoffitt Cancer Center Tampa, FL, USA
contact emaileric.haura@moffitt.org
lab head
John Koomen
contact affiliationMoffitt Cancer Center
contact emailjohn.koomen@moffitt.org
dataset submitter
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Dataset FTP location
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