دورية أكاديمية
Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
| العنوان: | Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation |
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| المؤلفون: | Andrio, Emilie, Lotte, Romain, Hamaoui, Daniel, Cherfils, Jacqueline, Doye, Anne, Daugaard, Mads, Sørensen, Poul, Bost, Frédéric, Ruimy, Raymond, Mettouchi, Amel, Lemichez, Emmanuel |
| المساهمون: | Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA), Toxines bactériennes dans la relation hôtes-pathogènes, Université Nice Sophia Antipolis (1965 - 2019) (UNS)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA), Laboratoire de Bactériologie CHU Nice, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital Archet 2 Nice (CHU), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), University of British Columbia (UBC), Vancouver Prostate Centre Vancouver General Hospital (VPC), Vancouver General Hospital, BC Cancer Agency Research Centre (BCCRC), Signalisation moléculaire et obésité, Université Nice Sophia Antipolis (1965 - 2019) (UNS)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by INSERM, CNRS and fundings from the Ligue Nationale Contre le Cancer (LNCC, équipe labellisée), Association pour la Recherche sur le Cancer (ARC-SFI20111203659 & ARC-SFI20111203671), a fellowship LNCC to D.H., a PhD fellowship from the “Fondation pour la Recherche Médicale” (FRM-FDM20150632804) to R.L., We are grateful to Melissa Sivaneson, Frédéric Reinier and Patrick Munro for technical help and fruitful discussions. We thank Orane Visvikis for critical reading of the manuscript. |
| المصدر: | ISSN: 2045-2322. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Proteolysis, Cell biology, MESH: Amino Acid Sequence, MESH: Cell Line, MESH: Models, Molecular, MESH: Mutant Proteins/chemistry, MESH: Mutation, Missense/genetics, MESH: Neoplasms/genetics, MESH: Protein Binding, MESH: Protein Domains, MESH: Structure-Activity Relationship, MESH: Ubiquitin-Protein Ligases/chemistry, MESH: Ubiquitin-Protein Ligases/genetics, MESH: Ubiquitin-Protein Ligases/metabolism, MESH: Ubiquitination, MESH: rac1 GTP-Binding Protein/metabolism, MESH: Cell Proliferation, MESH: Humans, [SDV]Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] |
| الوصف: | International audience ; The E3 ubiquitin ligase HACE1 is a potent tumor suppressor that controls cell proliferation and ubiquitylates the small GTPase Rac1 to target it to proteasomal degradation. Whether and how the activity of HACE1 is regulated by the N-terminal ankyrin (ANK) and the middle (MID) domains is ill defined. Here, we identified in the version 64 of the Catalogue of Somatic Mutations in Cancer (COSMIC) 13 missense mutations of hace1 located outside the HECT domain, and found that all lead to defective control of cell proliferation. In addition, several mutations located in the ankyrin domain displayed a dramatic reduction in Rac1 ubiquitylation associated with a decrease of colony formation in soft agar. 3D structure modelling of the 7 ankyrin-repeats coupled to functional analysis identified a surface epitope centered on one of the mutated residue, Gly-175, which is critical for controlling Rac1 binding and ubiquitylation. We also identified a role for the MID domain in conferring the specificity of association of HACE1 to the active form of Rac1. Our study of the functional interplay between HACE1 and Rac1 in cancer thus sheds a new light on the molecular mechanism of Rac1 ubiquitylation by HACE1 and the impact of its cancer-associated mutations in cell proliferation. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/28317937; pasteur-02448600; https://pasteur.hal.science/pasteur-02448600Test; https://pasteur.hal.science/pasteur-02448600/documentTest; https://pasteur.hal.science/pasteur-02448600/file/Identification_of_cancer_associated_missense_mutations.pdfTest; PUBMED: 28317937; PUBMEDCENTRAL: PMC5357957 |
| DOI: | 10.1038/srep44779 |
| الإتاحة: | https://doi.org/10.1038/srep44779Test https://pasteur.hal.science/pasteur-02448600Test https://pasteur.hal.science/pasteur-02448600/documentTest https://pasteur.hal.science/pasteur-02448600/file/Identification_of_cancer_associated_missense_mutations.pdfTest |
| حقوق: | http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.3105DA98 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/srep44779 |
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