title: The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins.
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 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.
authors.affiliation: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilluy
authors.forename: Vinay
authors.initials: V
authors.lastname: Swaminathan
authors.forename: Rafael
authors.initials: R
authors.lastname: Garcia-Mata
authors.forename: E Timothy
authors.initials: ET
authors.lastname: O'Brien
authors.forename: Richard
authors.initials: R
authors.lastname: Superfine
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D055595:Mechanical Phenomena; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors
chemical_list: C577223:Arhgef12 protein, mouse; C577402:Arhgef2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D064067:Rho Guanine Nucleotide Exchange Factors