IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251

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dc.contributor.authorRieger, Leonie
dc.contributor.authorO'Shea, Sandra
dc.contributor.authorGodsmark, Grant
dc.contributor.authorStanicka, Joanna
dc.contributor.authorKelly, Geraldine
dc.contributor.authorO'Connor, Rosemary
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2020-06-04T08:13:48Z
dc.date.available2020-06-04T08:13:48Z
dc.date.issued2020-05-26
dc.description.abstractAlthough insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the consequences of this phosphorylation, we generated phosphomimetic Y1250E/Y1251E (EE) and nonphosphorylatable Y1250F/Y1251F (FF) mutant forms of IGF-1R. Although fully competent in kinase activity and signaling, the EE mutant was more rapidly internalized and degraded than either the wild-type or FF receptor. IGF-1 promoted the accumulation of wild-type and EE IGF-1R within the Golgi apparatus, whereas the FF mutant remained at the plasma membrane. Golgi-associated IGF-1R signaling was a feature of migratory cancer cells, and Golgi disruption impaired IGF-1–induced signaling and cell migration. Upon the formation of new cell adhesions, IGF-1R transiently relocalized to the plasma membrane from the Golgi. Thus, phosphorylation at Tyr1250/1251 promoted IGF-1R translocation to and signaling from the Golgi to support an aggressive cancer phenotype. This process distinguishes IGF-1R from IR signaling and could contribute to the poor clinical efficacy of antibodies that target IGF-1R on the cell surface.en
dc.description.sponsorshipScience Foundation Ireland (Principal Investigator Award 16/A/4505)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRieger, L., O’Shea, S., Godsmark, G., Stanicka, J., Kelly, G. and O’Connor, R. (2020) ‘IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251’, Science Signaling, 13(633), eaba3176. doi: 10.1126/scisignal.aba3176en
dc.identifier.doi10.1126/scisignal.aba3176en
dc.identifier.eissn1937-9145
dc.identifier.issn1945-0877
dc.identifier.issued633en
dc.identifier.journaltitleScience Signalingen
dc.identifier.urihttps://hdl.handle.net/10468/10125
dc.identifier.volume13en
dc.language.isoenen
dc.publisherAmerican Association for the Advancement of Scienceen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Principal Investigator Programme (PI)/11/PI/1139/IE/IGF-I Receptor signalling and regulation/en
dc.rights© 2020, the Authors. Published under license by the American Association for the Advancement of Science. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling 13(633) on 26 May 2020, doi: 10.1126/scisignal.aba3176en
dc.subjectInsulin-like growth factor 1en
dc.subjectIGF-1en
dc.subjectIGF-1Ren
dc.subjectTyrosineen
dc.subjectTyr1250en
dc.subjectTyr1251en
dc.subjectTyr1250/1251en
dc.subjectCell adhesionen
dc.subjectCanceren
dc.subjectTumoren
dc.subjectGolgien
dc.titleIGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251en
dc.typeArticle (peer-reviewed)en
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