Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Sperka, Tobias, Geißler, Katja J., Merkel, Ulrike, Scholl, Ingmar, Rubio, Ignacio, Herrlich, Peter, Morrison, Helen L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
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
_version_ 1782217119301107712
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
work_keys_str_mv AT sperkatobias activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT geißlerkatjaj activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT merkelulrike activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT schollingmar activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT rubioignacio activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT herrlichpeter activationofrasrequirestheermdependentlinkofactintotheplasmamembrane
AT morrisonhelenl activationofrasrequirestheermdependentlinkofactintotheplasmamembrane