Covalent dimerization of interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI) facilitates EMT, invasion, and late aspects of metastasis

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dc.authorid0000-0001-7139-9010
dc.contributor.authorKral, Maria
dc.contributor.authorKlimek, Christoph
dc.contributor.authorKutay, Betül
dc.contributor.authorTimelthaler, Gerald
dc.contributor.authorLendl, Thomas
dc.contributor.authorNeuditschko, Benjamin
dc.contributor.authorGerner, Christopher
dc.contributor.authorSibilia, Maria
dc.contributor.authorCsiszar, Agnes
dc.date.accessioned2024-05-10T11:25:14Z
dc.date.available2024-05-10T11:25:14Z
dc.date.issued2017
dc.departmentTAÜ, Fen Fakültesi, Moleküler Biyoteknoloji Bölümüen_US
dc.description.abstractThe interleukin-like epithelial-to-mesenchymal transition (EMT) inducer(ILEI)/FAM3C is a member of the highly homologous FAM3 family andis essential for EMT and metastasis formation. It is upregulated in severalcancers, and its altered subcellular localization strongly correlates withpoor survival. However, the mechanism of ILEI action, including the struc-tural requirements for ILEI activity, remains elusive. Here, we show thatILEI formed both monomers and covalent dimers in cancer cell lines andin tumors. Using mutational analysis and pulse-chase experiments, wefound that the four ILEI cysteines, conserved throughout the FAM3 fam-ily and involved in disulfide bond formation were essential for extracellularILEI accumulation in cultured cells. Modification of a fifth cysteine(C185), unique for ILEI, did not alter protein secretion, but completelyinhibited ILEI dimerization. Wild-type ILEI monomers, but not C185Amutants, could be converted into covalent dimers extracellularly uponoverexpression by intramolecular-to-intermolecular disulfide bond isomer-ization. Incubation of purified ILEI with cell culture medium showed thatdimerization was triggered by bovine serum in a dose- and time-dependentmanner. Purified ILEI dimers induced EMT and trans-well invasion ofcancer cellsin vitro. In contrast, ILEI monomers and the dimerization-defective C185A mutant affected only cell motility as detected by scratchassays and cell tracking via time-lapse microscopy. Importantly, tumorcells overexpressing wild-type ILEI caused large tumors and lung metas-tases in nude mice, while cells overexpressing the dimerization-defectiveC185A mutant behaved similar to control cells. These data show that cova-lent ILEI self-assembly is essential for EMT induction, elevated tumorgrowth, and metastasis.
dc.identifier.citationKral, M., Klimek, C., Kutay, B., Timelthaler, G., Lendl, T., Neuditschko, B., Gerner, C., Sibilia, M., Csiszar, A. (2017). Covalent dimerization of interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI) facilitates EMT, invasion, and late aspects of metastasis. Federation of European Biochemical Societies, 284 (20), 3484-3505.
dc.identifier.doi10.1111/febs.14207
dc.identifier.endpage3505en_US
dc.identifier.issue20en_US
dc.identifier.startpage3484en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12846/1233
dc.identifier.volume284en_US
dc.language.isoen
dc.relation.ispartofFederation of European Biochemical Societies
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectCancer metastasisen_US
dc.subjectCovalent dimerizationen_US
dc.subjectEMTen_US
dc.subjectFAM3Cen_US
dc.subjectILEIen_US
dc.titleCovalent dimerization of interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI) facilitates EMT, invasion, and late aspects of metastasis
dc.typeArticle

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