The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling

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dc.contributor.authorAsbagh, Layka Abbasi
dc.contributor.authorVázquez Urio, Iria
dc.contributor.authorVecchione, Loredana
dc.contributor.authorBudinska, Eva
dc.contributor.authorDe Vriendt, Veerle
dc.contributor.authorBaietti, Maria Francesca
dc.contributor.authorSteklov, Mikhail
dc.contributor.authorJacobs, Bart
dc.contributor.authorHoe, Nicholas
dc.contributor.authorSingh, Sharat
dc.contributor.authorImjeti, Naga-Sailaja
dc.contributor.authorZimmermann, Pascale
dc.contributor.authorSablina, Anna
dc.contributor.authorTejpar, Sabine
dc.contributor.departmentCienciases_ES
dc.contributor.departmentZientziakeu
dc.date.accessioned2025-01-13T17:25:48Z
dc.date.available2025-01-13T17:25:48Z
dc.date.issued2014-10-11
dc.date.updated2025-01-13T17:10:24Z
dc.description.abstractInappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.en
dc.description.sponsorshipThis work was supported by the KU Leuven GOA/12/016 (ST, PZ), the EU FP7 program grant COLTHERES (ST, LAA), Research Foundation Flanders - FWO (AAS, ST, MFB, BJ) and the Belgian National Cancer Plan (ST).
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAsbagh, L. A., Vazquez, I., Vecchione, L., Budinska, E., De Vriendt, V., Baietti, M.F., Steklov, M., Jacobs, B., Hoe, N., Singh, S., Imjeti, N.-S., Zimmermann, P., Sablina, A., Tejpar, S. (2014) The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling. Oncotarget, 5(20), 10070-10083. https://doi.org/10.18632/oncotarget.2458.
dc.identifier.doi10.18632/oncotarget.2458
dc.identifier.issn1949-2553
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52904
dc.language.isoeng
dc.publisherImpact Journals
dc.relation.ispartofOncotarget 2014, 5(20), 10070-10083
dc.relation.publisherversionhttps://doi.org/10.18632/oncotarget.2458
dc.rightsOncotarget applies the Creative Commons Attribution License (CC BY 4.0) to all works we publish (read the human-readable summary or the full license legal code).
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectColon canceren
dc.subjectEGFRen
dc.subjectEGFR inhibitoren
dc.subjectPhosphataseen
dc.subjectPTPROen
dc.subjectSRC kinaseen
dc.titleThe tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signalingen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication3762d67a-d18f-4f29-8eee-8b4c20793cd8
relation.isAuthorOfPublication.latestForDiscovery3762d67a-d18f-4f29-8eee-8b4c20793cd8

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