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Signaling through the leukocyte integrin LFA-1 in T cells induces a transient activation of Rac-1 that is regulated by Vav and PI3K/Akt-1

AuthorsSánchez-Martín, Lorena; Sánchez-Sánchez, Noelia; Gutiérrez-López, María Dolores ; Rojo, Ana I. ; Vicente, Miguel; Pérez-Álvarez, María José ; Sánchez-Mateos, Paloma; Bustelo, Xosé R. ; Cuadrado, Antonio ; Sánchez-Madrid, Francisco; Rodríguez-Fernández, José Luis ; Cabañas, Carlos
Issue Date16-Apr-2004
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJ Biol Chem. 279(16):16194-205 ( 2004)
AbstractIntegrin LFA-1 is a receptor that is able to transmit multiple intracellular signals in leukocytes. Herein we show that LFA-1 induces a potent and transient increase in the activity of the small GTPase Rac-1 in T cells. Maximal Rac-1 activity peaked 10-15 min after LFA-1 stimulation and rapidly declined to basal levels at longer times. We have identified Vav, a guanine nucleotide exchange factor for Rac-1, and PI3K/Akt, as regulators of the activation and inactivation phases of the activity of Rac-1, respectively, in the context of LFA-1 signaling based on the following experimental evidence: (i) LFA-1 induced activation of Vav and PI3K/Akt with kinetics consistent with a regulatory role for these molecules on Rac-1, (ii) overexpression of a constitutively active Vav mutant induces activation of Rac independently of LFA-1 stimulation whereas overexpression of a dominant-negative Vav mutant blocks LFA-1-mediated Rac activation, (iii) pharmacological inhibition of PI3K/Akt prevented the fall in the activity of Rac-1 after its initial activation but had no effect on Vav activity, and (iv) overexpression of a dominant-negative or a constitutively active Akt-1 induced or inhibited, respectively, Rac-1 activity. Finally, we show that T cells with a sustained Rac activity have impaired capacity to elongate onto ICAM-1. These results demonstrate that down-regulation of the activity of this GTPase is a requirement for the regulation of T cell morphology and motility and highlight the importance of temporal regulation of the signaling triggered from this integrin.
Description12 p.-8 fig.
Publisher version (URL)http://www.jbc.org/content/279/16/16194.long
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