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Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation

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....

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Autores principales: Andrio, Emilie, Lotte, Romain, Hamaoui, Daniel, Cherfils, Jacqueline, Doye, Anne, Daugaard, Mads, Sorensen, Poul H., Bost, Frédéric, Ruimy, Raymond, Mettouchi, Amel, Lemichez, Emmanuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357957/
https://www.ncbi.nlm.nih.gov/pubmed/28317937
http://dx.doi.org/10.1038/srep44779
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author Andrio, Emilie
Lotte, Romain
Hamaoui, Daniel
Cherfils, Jacqueline
Doye, Anne
Daugaard, Mads
Sorensen, Poul H.
Bost, Frédéric
Ruimy, Raymond
Mettouchi, Amel
Lemichez, Emmanuel
author_facet Andrio, Emilie
Lotte, Romain
Hamaoui, Daniel
Cherfils, Jacqueline
Doye, Anne
Daugaard, Mads
Sorensen, Poul H.
Bost, Frédéric
Ruimy, Raymond
Mettouchi, Amel
Lemichez, Emmanuel
author_sort Andrio, Emilie
collection PubMed
description 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.
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spelling pubmed-53579572017-03-22 Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation Andrio, Emilie Lotte, Romain Hamaoui, Daniel Cherfils, Jacqueline Doye, Anne Daugaard, Mads Sorensen, Poul H. Bost, Frédéric Ruimy, Raymond Mettouchi, Amel Lemichez, Emmanuel Sci Rep Article 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. Nature Publishing Group 2017-03-20 /pmc/articles/PMC5357957/ /pubmed/28317937 http://dx.doi.org/10.1038/srep44779 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Andrio, Emilie
Lotte, Romain
Hamaoui, Daniel
Cherfils, Jacqueline
Doye, Anne
Daugaard, Mads
Sorensen, Poul H.
Bost, Frédéric
Ruimy, Raymond
Mettouchi, Amel
Lemichez, Emmanuel
Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title_full Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title_fullStr Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title_full_unstemmed Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title_short Identification of cancer-associated missense mutations in hace1 that impair cell growth control and Rac1 ubiquitylation
title_sort identification of cancer-associated missense mutations in hace1 that impair cell growth control and rac1 ubiquitylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357957/
https://www.ncbi.nlm.nih.gov/pubmed/28317937
http://dx.doi.org/10.1038/srep44779
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