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J. Biol. Chem., Vol. 279, Issue 16, 16194-16205, April 16, 2004

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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^*

Lorena Sánchez-Martín, Noelia Sánchez-Sánchez, M. Dolores Gutiérrez-López, Ana I. Rojo¶, Miguel Vicente-Manzanares||, María José Pérez-Alvarez, Paloma Sánchez-Mateos**, Xosé R. Bustelo, Antonio Cuadrado¶, Francisco Sánchez-Madrid||, José Luis Rodríguez-Fernández, and Carlos Cabañas||¶¶

From the Instituto de Farmacología y Toxicología (CSIC-UCM), Facultad de Medicina UCM, Madrid 28040, ^¶Departamento de Bioquímica (CSIC-UAM), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, ^**Sección de Inmuno-Oncología, Hospital Gregorio Marañón, Madrid 28007, ^||Servicio de Inmunología, Hospital de la Princesa, Madrid 28006, and Centro de Investigación del Cáncer (CSIC-USAL), Universidad de Salamanca, Salamanca 37007, Spain

Integrin 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.

Received for publication, January 28, 2004

^* This work was supported in part by Grants CICYT SAF 2001–2807 from Ministerio de Ciencia y Tecnología and FIS-01/1367 from Ministerio de Sanidad y Consumo (to C. C.), a fellowship from Comunidad de Madrid (to L. S.-M.), a Formación de Profesorado Universitario predoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to N. S.-S.), and a postdoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to M. D. G.-L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Contributed equally to this work.

Senior author. Contributed equally to this work.

^¶¶ To whom all correspondence should be addressed: Instituto de Farmacología y Toxicología (CSIC-UCM), Facultad de Medicina UCM, Pabellón III, Madrid 28040, Spain. Tel.: 34-91-3941444; Fax: 34-91-3941470; E-mail: cacabagu{at}med.ucm.es.

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