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Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15

The opposing regulators of ubiquitylation status, E3 ligases and deubiquitylases, are often found to be associated in complexes. Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related...

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Autores principales: Hayes, Sebastian D., Liu, Han, MacDonald, Ewan, Sanderson, Christopher M., Coulson, Judy M., Clague, Michael J., Urbé, Sylvie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522295/
https://www.ncbi.nlm.nih.gov/pubmed/23105109
http://dx.doi.org/10.1074/jbc.M112.386938
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author Hayes, Sebastian D.
Liu, Han
MacDonald, Ewan
Sanderson, Christopher M.
Coulson, Judy M.
Clague, Michael J.
Urbé, Sylvie
author_facet Hayes, Sebastian D.
Liu, Han
MacDonald, Ewan
Sanderson, Christopher M.
Coulson, Judy M.
Clague, Michael J.
Urbé, Sylvie
author_sort Hayes, Sebastian D.
collection PubMed
description The opposing regulators of ubiquitylation status, E3 ligases and deubiquitylases, are often found to be associated in complexes. Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. We map the interaction to the N-terminal DUSP-UBL domain of USP15 and the coiled coil region of BRAP. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. Importantly, USP15 but not USP4 depletion destabilizes BRAP by promoting its proteasomal degradation, and BRAP-protein levels can be rescued by reintroducing catalytically active but not inactive mutant USP15. Unexpectedly, USP15 depletion results in a decrease in amplitude of MAPK signaling in response to EGF and PDGF. We provide evidence for a model in which the dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of a negative regulator, the E3 ligase BRAP.
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spelling pubmed-35222952012-12-18 Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15 Hayes, Sebastian D. Liu, Han MacDonald, Ewan Sanderson, Christopher M. Coulson, Judy M. Clague, Michael J. Urbé, Sylvie J Biol Chem Signal Transduction The opposing regulators of ubiquitylation status, E3 ligases and deubiquitylases, are often found to be associated in complexes. Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. We map the interaction to the N-terminal DUSP-UBL domain of USP15 and the coiled coil region of BRAP. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. Importantly, USP15 but not USP4 depletion destabilizes BRAP by promoting its proteasomal degradation, and BRAP-protein levels can be rescued by reintroducing catalytically active but not inactive mutant USP15. Unexpectedly, USP15 depletion results in a decrease in amplitude of MAPK signaling in response to EGF and PDGF. We provide evidence for a model in which the dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of a negative regulator, the E3 ligase BRAP. American Society for Biochemistry and Molecular Biology 2012-12-14 2012-10-26 /pmc/articles/PMC3522295/ /pubmed/23105109 http://dx.doi.org/10.1074/jbc.M112.386938 Text en © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Signal Transduction
Hayes, Sebastian D.
Liu, Han
MacDonald, Ewan
Sanderson, Christopher M.
Coulson, Judy M.
Clague, Michael J.
Urbé, Sylvie
Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title_full Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title_fullStr Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title_full_unstemmed Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title_short Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15
title_sort direct and indirect control of mitogen-activated protein kinase pathway-associated components, brap/imp e3 ubiquitin ligase and craf/raf1 kinase, by the deubiquitylating enzyme usp15
topic Signal Transduction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522295/
https://www.ncbi.nlm.nih.gov/pubmed/23105109
http://dx.doi.org/10.1074/jbc.M112.386938
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