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Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane
BACKGROUND: Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras. PRINCIPAL FINDINGS: We can now demonstra...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221661/ https://www.ncbi.nlm.nih.gov/pubmed/22132106 http://dx.doi.org/10.1371/journal.pone.0027511 |
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author | Sperka, Tobias Geißler, Katja J. Merkel, Ulrike Scholl, Ingmar Rubio, Ignacio Herrlich, Peter Morrison, Helen L. |
author_facet | Sperka, Tobias Geißler, Katja J. Merkel, Ulrike Scholl, Ingmar Rubio, Ignacio Herrlich, Peter Morrison, Helen L. |
author_sort | Sperka, Tobias |
collection | PubMed |
description | BACKGROUND: Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras. PRINCIPAL FINDINGS: We can now demonstrate that the activation of Ras requires, in addition, the essential participation of ezrin, radixin and/or moesin (ERM), a family of actin-binding proteins, and of actin. Disrupting either the interaction of the ERM proteins with co-receptors, down-regulation of ERM proteins by siRNA, expression of dominant-negative mutants of the ERM proteins or disruption of F-actin, abolishes growth factor-induced Ras activation. Ezrin/actin catalyzes the formation of a multiprotein complex consisting of RTK, co-receptor, Grb2, SOS and Ras. We also identify binding sites for both Ras and SOS on ezrin; mutations of these binding sites destroy the interactions and inhibit Ras activation. Finally, we show that the formation of the ezrin-dependent complex is necessary to enhance the catalytic activity of SOS and thereby Ras activation. CONCLUSIONS: Taking these findings together, we propose that the ERM proteins are novel scaffolds at the level of SOS activity control, which is relevant for both normal Ras function and dysfunction known to occur in several human cancers. |
format | Online Article Text |
id | pubmed-3221661 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32216612011-11-30 Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane Sperka, Tobias Geißler, Katja J. Merkel, Ulrike Scholl, Ingmar Rubio, Ignacio Herrlich, Peter Morrison, Helen L. PLoS One Research Article BACKGROUND: Receptor tyrosine kinases (RTKs) participate in a multitude of signaling pathways, some of them via the small G-protein Ras. An important component in the activation of Ras is Son of sevenless (SOS), which catalyzes the nucleotide exchange on Ras. PRINCIPAL FINDINGS: We can now demonstrate that the activation of Ras requires, in addition, the essential participation of ezrin, radixin and/or moesin (ERM), a family of actin-binding proteins, and of actin. Disrupting either the interaction of the ERM proteins with co-receptors, down-regulation of ERM proteins by siRNA, expression of dominant-negative mutants of the ERM proteins or disruption of F-actin, abolishes growth factor-induced Ras activation. Ezrin/actin catalyzes the formation of a multiprotein complex consisting of RTK, co-receptor, Grb2, SOS and Ras. We also identify binding sites for both Ras and SOS on ezrin; mutations of these binding sites destroy the interactions and inhibit Ras activation. Finally, we show that the formation of the ezrin-dependent complex is necessary to enhance the catalytic activity of SOS and thereby Ras activation. CONCLUSIONS: Taking these findings together, we propose that the ERM proteins are novel scaffolds at the level of SOS activity control, which is relevant for both normal Ras function and dysfunction known to occur in several human cancers. Public Library of Science 2011-11-21 /pmc/articles/PMC3221661/ /pubmed/22132106 http://dx.doi.org/10.1371/journal.pone.0027511 Text en Sperka et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sperka, Tobias Geißler, Katja J. Merkel, Ulrike Scholl, Ingmar Rubio, Ignacio Herrlich, Peter Morrison, Helen L. Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title | Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title_full | Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title_fullStr | Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title_full_unstemmed | Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title_short | Activation of Ras Requires the ERM-Dependent Link of Actin to the Plasma Membrane |
title_sort | activation of ras requires the erm-dependent link of actin to the plasma membrane |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221661/ https://www.ncbi.nlm.nih.gov/pubmed/22132106 http://dx.doi.org/10.1371/journal.pone.0027511 |
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