PXD033912

PXD033912 is an original dataset announced via ProteomeXchange.

Title	Systematic Integration of the Cancer Related Genetic Landscape of Eph Receptors and Ephrins with Proteomics Reveals a Functional Crosstalk between EPHB6 and EGF Receptors
Description	Aberrant activities of fourteen Eph receptor tyrosine kinases (RTKs) and their eight ephrin ligands are often observed in human malignancies, where they control cancer development, progression, and aggressiveness. While multiple attempts have been made to target Eph receptors in tumors, their effectiveness has been hindered by distinct contexts in which these proteins operate to enhance or suppress the disease. One of the strategies to overcoming this challenge is to define the molecular landscape/genetic interactions (GIs) associated with pro- and anti-malignant activities of Ephs and ephrins, as this should outline context-specific genetic dependencies associated with these molecules. Here, we used a multi-step bioinformatics analysis of the TCGA database and the DepMap gene essentiality data from cancer cell lines to construct a network of GIs of Ephs and ephrins in human malignancies. Validation of the relevance of this network was centered on an unusual Eph receptor EPHB6, which is innately kinase-incompetent, but nevertheless, actively controls aggressiveness and tumor initiation in several cancer types. To select the most relevant GI from the generated network, we performed genome-wide screening and EPHB6 BioID analysis. While, the BioID approach pointed towards EPHB6 interactions with several RTKs, including all kinase-active members of the EGFR/ErbB class, its integration with shRNA screening and computationally predicted GIs, unambiguously pointed towards EGFR as a key EPHB6 partner. Indeed, our further experiments confirmed EPHB6 interactions with all kinase-competent ErbBs, including EGFR, and revealed its ability to modulate EGF-induced EGFR tyrosine phosphorylation and downstream signaling. This ultimately, enhanced proliferation of cancer cells, culminating in efficient tumor development. In agreement, we found high levels of EGFR to positively correlate with higher EPHB6 expression in several tumor types. Taken together, these observations indicate that EPHB6 should serve as an effective target in tumors with high EGFR levels and that co-targeting these receptors might provide therapeutic benefits. More importantly, these experiments provide a strong support for the relevance of our computational strategy and suggest that the generated network describing GIs of Eph receptors and their ligands is a valuable resource that can be used for developing new treatment approaches aiming to hunt these proteins in human malignancies.
HostingRepository	PRIDE
AnnounceDate	2023-05-16
AnnouncementXML	Submission_2023-05-16_10:40:19.519.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD033912
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Sara LuizaBanerjee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-16 07:00:30	ID requested
⏵ 1	2023-05-16 10:40:19	announced

10.6019/PXD033912;

submitter keyword: EPHB6 receptor

BioID

proximity proteomics

NicolasBisson
contact affiliation	Centre de recherche du Centre Hospitalier Universitaire (CHU) de Quebec-Université Laval, Québec, QC, Canada Centre de recherche sur le cancer de l’Université Laval, Québec, QC, Canada PROTEO-Quebec Network for Research on Protein Function, Engineering, and Applications, Québec, QC, Canada Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC, Canada
contact email	Nick.Bisson@crchudequebec.ulaval.ca
lab head
Sara LuizaBanerjee
contact affiliation	Institut de recherches cliniques de Montréal - McGill University
contact email	banerjee.sara@gmail.com
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/2023/05/PXD033912

PRIDE project URI

• PRIDE
  1. PXD033912
     1. Label: PRIDE project
     2. Name: Systematic Integration of the Cancer Related Genetic Landscape of Eph Receptors and Ephrins with Proteomics Reveals a Functional Crosstalk between EPHB6 and EGF Receptors