FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion

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dc.contributor.authorStanicka, Joanna
dc.contributor.authorRieger, Leonie
dc.contributor.authorO'Shea, Sandra
dc.contributor.authorCox, Orla T.
dc.contributor.authorColeman, Michael
dc.contributor.authorO'Flanagan, Ciara
dc.contributor.authorAddario, Barbara
dc.contributor.authorMcCabe, Nuala
dc.contributor.authorKennedy, Richard
dc.contributor.authorO'Connor, Rosemary
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderSeventh Framework Programmeen
dc.contributor.funderFP7 People: Marie-Curie Actionsen
dc.date.accessioned2018-11-09T12:00:40Z
dc.date.available2018-11-09T12:00:40Z
dc.date.issued2018-03-15
dc.date.updated2018-11-09T08:42:14Z
dc.description.abstractIGF-1 receptor (IGF-1R) and integrin cooperative signaling promotes cancer cell survival, proliferation, and motility, but whether this influences cancer progression and therapy responses is largely unknown. Here we investigated the non-receptor tyrosine adhesion kinase FES-related (FER), following its identification as a potential mediator of sensitivity to IGF-1R kinase inhibition in a functional siRNA screen. We found that FER and the IGF-1R co-locate in cells and can be co-immunoprecipitated. Ectopic FER expression strongly enhanced IGF-1R expression and phosphorylation on tyrosines 950 and 1131. FER phosphorylated these sites in an IGF-1R kinase-independent manner and also enhanced IGF-1-mediated phosphorylation of SHC, and activation of either AKT or MAPK-signaling pathways in different cells. The IGF-1R, β1 Integrin, FER, and its substrate cortactin were all observed to co-locate in cell adhesion complexes, the disruption of which reduced IGF-1R expression and activity. High FER expression correlates with phosphorylation of SHC in breast cancer cell lines and with a poor prognosis in patient cohorts. FER and SHC phosphorylation and IGF-1R expression could be suppressed with a known anaplastic lymphoma kinase inhibitor (AP26113) that shows high specificity for FER kinase. Overall, we conclude that FER enhances IGF-1R expression, phosphorylation, and signaling to promote cooperative growth and adhesion signaling that may facilitate cancer progression.en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationStanicka, J., Rieger, L., O’Shea, S., Cox, O., Coleman, M., O’Flanagan, C., Addario, B., McCabe, N., Kennedy, R. and O’Connor, R. (2018) 'FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion', Oncogene, 37(23), pp. 3131-3150. doi: 10.1038/s41388-017-0113-zen
dc.identifier.doi10.1038/s41388-017-0113-z
dc.identifier.endpage3150en
dc.identifier.issn0950-9232
dc.identifier.journaltitleOncogeneen
dc.identifier.startpage3131en
dc.identifier.urihttps://hdl.handle.net/10468/7082
dc.identifier.volume37en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/11/PI/1139/IE/IGF-I Receptor signalling and regulation/en
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/251480/EU/Identification of Clinically Useful Biomarkers for IGF-I Receptor Signalling n Cancer/BIOMARKERIGFen
dc.relation.urihttps://www.nature.com/articles/s41388-017-0113-z
dc.rights© Macmillan Publishers Limited, part of Springer Nature 2018en
dc.subjectBreast canceren
dc.subjectCortactin phosphorylationen
dc.subjectCarcinoma cellsen
dc.subjectIGF-1 receptoren
dc.subjectResistanceen
dc.subjectProteinen
dc.subjectSRCen
dc.subjectMetastasisen
dc.subjectExpressionen
dc.subjectMigrationen
dc.titleFES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesionen
dc.typeArticle (peer-reviewed)en
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