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EGF receptor mediates adhesion-dependent activation of the Rac GTPase: a role for phosphatidylinositol 3-kinase and Vav2

Oncogene volume 22, pages 6100–6106 (2003)Cite this article

Abstract

Organization of the actin cytoskeleton in eucaryotic cells is controlled by small GTPases of the Rho family. Rac becomes activated by growth factor stimulation and integrin-mediated cell adhesion to extracellular matrix and is known to have a crucial role in lamellipodia formation, cell spreading and migration. At present, the intracellular pathways that connect cell surface receptors to Rac activation are poorly characterized. It has been reported previously that integrin-mediated cell attachment induces activation of the EGF receptor (EGFR) in the absence of EGF. We demonstrate here that this activation is instrumental for integrin-dependent Rac activation. Thus, we found that cells in which EGFR activity had been inhibited failed to spread and form lamellipodia on fibronectin. Failure to spread coincided with inhibition of adhesion-induced GTP loading of Rac and also with inhibition of the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Subsequent studies demonstrated that an activated form of PI 3-kinase restored Rac GTP loading in the presence of EGFR inhibition, while a dominant-negative form of PI 3-kinase blocked Rac GTP loading in fibronectin-adherent cells. Our further functional studies identified Vav2, a known exchange factor for Rac, as a crucial downstream component in EGFR- and PI 3-kinase-dependent Rac activation upon integrin-mediated cell adhesion. Our results provide a mechanistic insight into integrin-dependent Rac activation, and identify a novel role for EGFR, PI 3-kinase and Vav2 in this pathway.

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Acknowledgements

We wish to thank Drs Bob Abraham, Keith Burridge, Christopher Carpenter, Paola Defilippi, Filippo Giancotti, Alan Hall, Jerrold Olefsky and Xiaolan Qian for reagents used in this study, and members of the Vuori lab for helpful discussion and technical advice. This study was supported by grants from the National Institutes of Health (to KV) and by a postdoctoral fellowship from FCAR, Canada (to NM).

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  1. Cancer Research Center, The Burnham Institute, 10901 N Torrey Pines Road, La Jolla, 92037, CA, USA

    Nathaly Marcoux & Kristiina Vuori

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  1. Nathaly Marcoux
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  2. Kristiina Vuori
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Correspondence to Kristiina Vuori.

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Marcoux, N., Vuori, K. EGF receptor mediates adhesion-dependent activation of the Rac GTPase: a role for phosphatidylinositol 3-kinase and Vav2. Oncogene 22, 6100–6106 (2003). https://doi.org/10.1038/sj.onc.1206712

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