An engineered transforming growth factor ß (TGF-ß) monomer that functions as a dominant negative to block TGF-ß signaling

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dc.contributor.authorKim, Sun Kyung
dc.contributor.authorBarron, Lindsey
dc.contributor.authorHinck, Cynthia S.
dc.contributor.authorPetrunak, Elyse M.
dc.contributor.authorCano, Kristin E.
dc.contributor.authorThangirala, Avinash
dc.contributor.authorIskra, Brian
dc.contributor.authorBrothers, Molly
dc.contributor.authorVonberg, Machell
dc.contributor.authorLeal, Belinda
dc.contributor.authorRichter, Blair
dc.contributor.authorKodali, Ravindra
dc.contributor.authorTaylor, Alexander B.
dc.contributor.authorDu, Shoucheng
dc.contributor.authorBarnes, Christopher O.
dc.contributor.authorSulea, Traian
dc.contributor.authorCalero, Guillermo
dc.contributor.authorHart, P. John
dc.contributor.authorHart, Matthew J.
dc.contributor.authorDemeler, Borries
dc.contributor.authorHinck, Andrew P.
dc.date.accessioned2021-08-20T16:38:32Z
dc.date.available2021-08-20T16:38:32Z
dc.date.issued2017
dc.descriptionOpen access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesen_US
dc.description.abstractThe transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a Ki of 20–70 nm. Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI, enabled it to bind endogenous TβRII but prevented it from binding and recruiting TβRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-β signaling and may inform similar modifications of other TGF-β family members.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationKim, S. K., Barron, L., Hinck, C. S., Petrunak, E. M., Cano, K. E., Thangirala, A., Iskra, B., Brothers, M., Vonberg, M., Leal, B., Richter, B., Kodali, R., Taylor, A. B., Du, S., Barnes, C. O., Sulea, T., Calero, G., Hart, P. J., Hart, M. J.,...Hinck, A. P. (2017). An engineered transforming growth factor ß (TGF-ß) monomer that functions as a dominant negative to block TGF-ß signaling. Journal of Biological Chemistry, 292(17), 7173-7188. https://doi.org/10.1074/jbc.M116.768754en_US
dc.identifier.urihttps://hdl.handle.net/10133/6005
dc.language.isoen_USen_US
dc.publisherASBMB Publicationsen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of Pittsburgh School of Medicineen_US
dc.publisher.institutionUniversity of Texas Health Science Center at San Antonioen_US
dc.publisher.institutionNational Research Council Canadaen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1074/jbc.M116.768754en_US
dc.subjectCell signalingen_US
dc.subjectInhibitoren_US
dc.subjectTransforming growth factor betaen_US
dc.subjectTGF-ßen_US
dc.subjectDominant negativeen_US
dc.subject.lcshCancer
dc.subject.lcshFibrosis
dc.subject.lcshProtein engineering
dc.subject.lcshTransforming growth factors-beta
dc.titleAn engineered transforming growth factor ß (TGF-ß) monomer that functions as a dominant negative to block TGF-ß signalingen_US
dc.typeArticleen_US
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