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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2012
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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. |
format | Online Article Text |
id | pubmed-3522295 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
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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