Advanced

The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins

Guilluy, Christophe; Swaminathan, Vinay LU ; Garcia-Mata, Rafael; O'Brien, E Timothy; Superfine, Richard and Burridge, Keith (2011) In Nature Cell Biology 13(6). p.722-727
Abstract

How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behaviour. The application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement. Although RhoA has been shown to play a role during reinforcement, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of... (More)

How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behaviour. The application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement. Although RhoA has been shown to play a role during reinforcement, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signalling cascade that includes FAK and Ras.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Cell Line, Fibroblasts/cytology, Guanine Nucleotide Exchange Factors/genetics, Integrins/metabolism, Mechanical Phenomena, Mice, Proto-Oncogene Proteins/genetics, Recombinant Proteins/genetics, Rho Guanine Nucleotide Exchange Factors
in
Nature Cell Biology
volume
13
issue
6
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:79957889032
ISSN
1465-7392
DOI
10.1038/ncb2254
language
English
LU publication?
no
id
584a480c-6eb8-4e7e-8901-770e152ed4f3
date added to LUP
2018-09-07 16:54:11
date last changed
2018-09-16 04:57:05
@article{584a480c-6eb8-4e7e-8901-770e152ed4f3,
  abstract     = {<p>How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behaviour. The application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement. Although RhoA has been shown to play a role during reinforcement, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signalling cascade that includes FAK and Ras.</p>},
  author       = {Guilluy, Christophe and Swaminathan, Vinay and Garcia-Mata, Rafael and O'Brien, E Timothy and Superfine, Richard and Burridge, Keith},
  issn         = {1465-7392},
  keyword      = {Animals,Cell Line,Fibroblasts/cytology,Guanine Nucleotide Exchange Factors/genetics,Integrins/metabolism,Mechanical Phenomena,Mice,Proto-Oncogene Proteins/genetics,Recombinant Proteins/genetics,Rho Guanine Nucleotide Exchange Factors},
  language     = {eng},
  number       = {6},
  pages        = {722--727},
  publisher    = {Nature Publishing Group},
  series       = {Nature Cell Biology},
  title        = {The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins},
  url          = {http://dx.doi.org/10.1038/ncb2254},
  volume       = {13},
  year         = {2011},
}