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

Research output: Contribution to journalLetter

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The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. / Guilluy, Christophe; Swaminathan, Vinay; Garcia-Mata, Rafael; O'Brien, E Timothy; Superfine, Richard; Burridge, Keith.

In: Nature Cell Biology, Vol. 13, No. 6, 06.2011, p. 722-727.

Research output: Contribution to journalLetter

Harvard

Guilluy, C, Swaminathan, V, Garcia-Mata, R, O'Brien, ET, Superfine, R & Burridge, K 2011, 'The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins', Nature Cell Biology, vol. 13, no. 6, pp. 722-727. https://doi.org/10.1038/ncb2254

APA

Guilluy, C., Swaminathan, V., Garcia-Mata, R., O'Brien, E. T., Superfine, R., & Burridge, K. (2011). The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nature Cell Biology, 13(6), 722-727. https://doi.org/10.1038/ncb2254

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MLA

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Author

Guilluy, Christophe ; Swaminathan, Vinay ; Garcia-Mata, Rafael ; O'Brien, E Timothy ; Superfine, Richard ; Burridge, Keith. / The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. In: Nature Cell Biology. 2011 ; Vol. 13, No. 6. pp. 722-727.

RIS

TY - JOUR

T1 - The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins

AU - Guilluy, Christophe

AU - Swaminathan, Vinay

AU - Garcia-Mata, Rafael

AU - O'Brien, E Timothy

AU - Superfine, Richard

AU - Burridge, Keith

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line

KW - Fibroblasts/cytology

KW - Guanine Nucleotide Exchange Factors/genetics

KW - Integrins/metabolism

KW - Mechanical Phenomena

KW - Mice

KW - Proto-Oncogene Proteins/genetics

KW - Recombinant Proteins/genetics

KW - Rho Guanine Nucleotide Exchange Factors

U2 - 10.1038/ncb2254

DO - 10.1038/ncb2254

M3 - Letter

VL - 13

SP - 722

EP - 727

JO - Nature Cell Biology

T2 - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 6

ER -