Cargando…

Grb2 monomer–dimer equilibrium determines normal versus oncogenic function

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to...

Descripción completa

Detalles Bibliográficos
Autores principales: Ahmed, Zamal, Timsah, Zahra, Suen, Kin M., Cook, Nathan P., Lee, Gilbert R., Lin, Chi-Chuan, Gagea, Mihai, Marti, Angel A., Ladbury, John E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491180/
https://www.ncbi.nlm.nih.gov/pubmed/26103942
http://dx.doi.org/10.1038/ncomms8354
_version_ 1782379596579078144
author Ahmed, Zamal
Timsah, Zahra
Suen, Kin M.
Cook, Nathan P.
Lee, Gilbert R.
Lin, Chi-Chuan
Gagea, Mihai
Marti, Angel A.
Ladbury, John E.
author_facet Ahmed, Zamal
Timsah, Zahra
Suen, Kin M.
Cook, Nathan P.
Lee, Gilbert R.
Lin, Chi-Chuan
Gagea, Mihai
Marti, Angel A.
Ladbury, John E.
author_sort Ahmed, Zamal
collection PubMed
description The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression.
format Online
Article
Text
id pubmed-4491180
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Pub. Group
record_format MEDLINE/PubMed
spelling pubmed-44911802015-07-08 Grb2 monomer–dimer equilibrium determines normal versus oncogenic function Ahmed, Zamal Timsah, Zahra Suen, Kin M. Cook, Nathan P. Lee, Gilbert R. Lin, Chi-Chuan Gagea, Mihai Marti, Angel A. Ladbury, John E. Nat Commun Article The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression. Nature Pub. Group 2015-06-24 /pmc/articles/PMC4491180/ /pubmed/26103942 http://dx.doi.org/10.1038/ncomms8354 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ 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 Article
Ahmed, Zamal
Timsah, Zahra
Suen, Kin M.
Cook, Nathan P.
Lee, Gilbert R.
Lin, Chi-Chuan
Gagea, Mihai
Marti, Angel A.
Ladbury, John E.
Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title_full Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title_fullStr Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title_full_unstemmed Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title_short Grb2 monomer–dimer equilibrium determines normal versus oncogenic function
title_sort grb2 monomer–dimer equilibrium determines normal versus oncogenic function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491180/
https://www.ncbi.nlm.nih.gov/pubmed/26103942
http://dx.doi.org/10.1038/ncomms8354
work_keys_str_mv AT ahmedzamal grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT timsahzahra grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT suenkinm grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT cooknathanp grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT leegilbertr grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT linchichuan grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT gageamihai grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT martiangela grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction
AT ladburyjohne grb2monomerdimerequilibriumdeterminesnormalversusoncogenicfunction