The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signalling axis

Scott, M. et al. (2021) The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signalling axis. Oncogene, 40(12), pp. 2243-2257. (doi: 10.1038/s41388-021-01704-w) (PMID:33649538)

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Abstract

Mdm2 antagonizes the tumor suppressor p53. Targeting the Mdm2-p53 interaction represents an attractive approach for the treatment of cancers with functional p53. Investigating mechanisms underlying Mdm2-p53 regulation is therefore important. The scaffold protein β-arrestin2 (β-arr2) regulates tumor suppressor p53 by counteracting Mdm2. β-arr2 nucleocytoplasmic shuttling displaces Mdm2 from the nucleus to the cytoplasm resulting in enhanced p53 signaling. β-arr2 is constitutively exported from the nucleus, via a nuclear export signal, but mechanisms regulating its nuclear entry are not completely elucidated. β-arr2 can be SUMOylated, but no information is available on how SUMO may regulate β-arr2 nucleocytoplasmic shuttling. While we found β-arr2 SUMOylation to be dispensable for nuclear import, we identified a non-covalent interaction between SUMO and β-arr2, via a SUMO interaction motif (SIM), that is required for β-arr2 cytonuclear trafficking. This SIM promotes association of β-arr2 with the multimolecular RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub that resides on the cytoplasmic filaments of the nuclear pore complex. Depletion of RanBP2/RanGAP1-SUMO levels result in defective β-arr2 nuclear entry. Mutation of the SIM inhibits β-arr2 nuclear import, its ability to delocalize Mdm2 from the nucleus to the cytoplasm and enhanced p53 signaling in lung and breast tumor cell lines. Thus, a β-arr2 SIM nuclear entry checkpoint, coupled with active β-arr2 nuclear export, regulates its cytonuclear trafficking function to control the Mdm2-p53 signaling axis.

Item Type:Articles
Additional Information:The Institut Cochin lab is part of the Who am I? laboratory of excellence (grant ANR-11-LABX-0071), funded by the “Investments for the Future” program operated by The French National Research Agency (grant ANR-11-IDEX-0005-01). This work was funded by grants from the Fondation ARC pour la Recherche sur le Cancer ("Projet ARC" to M.G.H.S.), Ligue contre le Cancer (to M.G.H.S.), Royal Society ("International Joint Project Scheme" to M.G.H.S. and G.S.B.), France Canada Research Fund (to M.G.H.S. and S.A.), CNRS and INSERM. E.B.T was funded by MESR and Fondation ARC pour la Recherche sur le Cancer doctoral fellowships.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Findlay, Mrs Jane
Authors: Scott, M., Blondel-Tepaz, E., Leverve, M., Sokrat, B., Paradis, J., Kosic, M., Saha, K., Auffray, C., Lima-Fernandes, E., Zamborlini, A., Poupon, A., Gaboury, L., Findlay, J., Baillie, G., Enslen, H., Bouvier, M., Angers, S., and Marullo, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Oncogene
Publisher:Springer Nature
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:01 March 2021
Copyright Holders:Copyright © 2021 The Author(s), under exclusive licence to Springer Nature Limited
First Published:First published in Oncogene 40(12): 2243-2257
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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