Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen

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• dc.contributor.author Giubilaro, Jenna
• dc.contributor.author Schuetz, Doris A.
• dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
• dc.contributor.author Namkung, Yoon
• dc.contributor.author Khoury, Etienne
• dc.contributor.author Lara Márquez, Mónica
• dc.contributor.author Campbell, Shirley
• dc.contributor.author Beautrait, Alexandre
• dc.contributor.author Armando, Sylvain
• dc.contributor.author Radresa, Olivier
• dc.contributor.author Duchaine, Jean
• dc.contributor.author Lamarche Vane, Nathalie
• dc.contributor.author Claing, Audrey
• dc.contributor.author Selent, Jana
• dc.contributor.author Bouvier, Michel
• dc.contributor.author Marinier, Anne
• dc.contributor.author Laporte, Stéphane A.
• dc.date.accessioned 2021-10-06T06:56:59Z
• dc.date.available 2021-10-06T06:56:59Z
• dc.date.issued 2021
• dc.description.abstract Internalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation in receptor trafficking can lead to aberrant signaling and cell behavior. Here, using an endosomal BRET-based assay in a high-throughput screen with the prototypical GPCR angiotensin II type 1 receptor (AT1R), we sought to identify receptor trafficking inhibitors from a library of ~115,000 small molecules. We identified a novel dual Ras and ARF6 inhibitor, which we named Rasarfin, that blocks agonist-mediated internalization of AT1R and other GPCRs. Rasarfin also potently inhibits agonist-induced ERK1/2 signaling by GPCRs, and MAPK and Akt signaling by EGFR, as well as prevents cancer cell proliferation. In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.
• dc.format.mimetype application/pdf
• dc.identifier.citation Giubilaro J, Schuetz DA, Stepniewski TM, Namkung Y, Khoury E, Lara-Márquez M, Campbell S, Beautrait A, Armando S, Radresa O, Duchaine J, Lamarche-Vane N, Claing A, Selent J, Bouvier M, Marinier A, Laporte SA. Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen. Nat Commun. 2021;12(1):4688. DOI: 10.1038/s41467-021-24968-y
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-021-24968-y
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/48573
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2021;12(1):4688
• dc.rights © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Hormone receptors
• dc.subject.keyword Screening
• dc.title Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion