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praja2 regulates KSR1 stability and mitogenic signaling

The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We d...

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Autores principales: Rinaldi, L, Delle Donne, R, Sepe, M, Porpora, M, Garbi, C, Chiuso, F, Gallo, A, Parisi, S, Russo, L, Bachmann, V, Huber, R G, Stefan, E, Russo, T, Feliciello, A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917648/
https://www.ncbi.nlm.nih.gov/pubmed/27195677
http://dx.doi.org/10.1038/cddis.2016.109
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author Rinaldi, L
Delle Donne, R
Sepe, M
Porpora, M
Garbi, C
Chiuso, F
Gallo, A
Parisi, S
Russo, L
Bachmann, V
Huber, R G
Stefan, E
Russo, T
Feliciello, A
author_facet Rinaldi, L
Delle Donne, R
Sepe, M
Porpora, M
Garbi, C
Chiuso, F
Gallo, A
Parisi, S
Russo, L
Bachmann, V
Huber, R G
Stefan, E
Russo, T
Feliciello, A
author_sort Rinaldi, L
collection PubMed
description The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency.
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spelling pubmed-49176482016-07-07 praja2 regulates KSR1 stability and mitogenic signaling Rinaldi, L Delle Donne, R Sepe, M Porpora, M Garbi, C Chiuso, F Gallo, A Parisi, S Russo, L Bachmann, V Huber, R G Stefan, E Russo, T Feliciello, A Cell Death Dis Original Article The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency. Nature Publishing Group 2016-05 2016-05-19 /pmc/articles/PMC4917648/ /pubmed/27195677 http://dx.doi.org/10.1038/cddis.2016.109 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. 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 Original Article
Rinaldi, L
Delle Donne, R
Sepe, M
Porpora, M
Garbi, C
Chiuso, F
Gallo, A
Parisi, S
Russo, L
Bachmann, V
Huber, R G
Stefan, E
Russo, T
Feliciello, A
praja2 regulates KSR1 stability and mitogenic signaling
title praja2 regulates KSR1 stability and mitogenic signaling
title_full praja2 regulates KSR1 stability and mitogenic signaling
title_fullStr praja2 regulates KSR1 stability and mitogenic signaling
title_full_unstemmed praja2 regulates KSR1 stability and mitogenic signaling
title_short praja2 regulates KSR1 stability and mitogenic signaling
title_sort praja2 regulates ksr1 stability and mitogenic signaling
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917648/
https://www.ncbi.nlm.nih.gov/pubmed/27195677
http://dx.doi.org/10.1038/cddis.2016.109
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