HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 279/16/16194    most recent M400905200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sánchez-Martín, L. Articles by Cabañas, C. Search for Related Content PubMed PubMed Citation Articles by Sánchez-Martín, L. Articles by Cabañas, C. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. M. Kuijk, J. M. Beekman, J. Koster, H. R. Waterham, J. Frenkel, and P. J. Coffer HMG-CoA reductase inhibition induces IL-1{beta} release through Rac1/PI3K/PKB-dependent caspase-1 activation Blood, November 1, 2008; 112(9): 3563 - 3573. [Abstract] [Full Text] [PDF]

				U. Sela, M. Dayan, R. Hershkoviz, O. Lider, and E. Mozes A Peptide That Ameliorates Lupus Up-Regulates the Diminished Expression of Early Growth Response Factors 2 and 3 J. Immunol., February 1, 2008; 180(3): 1584 - 1591. [Abstract] [Full Text] [PDF]

				M. Nakhaei-Nejad, A. M. Hussain, Q.-X. Zhang, and A. G. Murray Endothelial PI 3-kinase activity regulates lymphocyte diapedesis Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3608 - H3616. [Abstract] [Full Text] [PDF]

				S. M. Nurmi, M. Autero, A. K. Raunio, C. G. Gahmberg, and S. C. Fagerholm Phosphorylation of the LFA-1 Integrin beta2-Chain on Thr-758 Leads to Adhesion, Rac-1/Cdc42 Activation, and Stimulation of CD69 Expression in Human T Cells J. Biol. Chem., January 12, 2007; 282(2): 968 - 975. [Abstract] [Full Text] [PDF]

				J.-i. Suzuki, S. Yamasaki, J. Wu, G. A. Koretzky, and T. Saito The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation Blood, January 1, 2007; 109(1): 168 - 175. [Abstract] [Full Text] [PDF]

				D. N. Atapattu and C. J. Czuprynski Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway Infect. Immun., September 1, 2005; 73(9): 5504 - 5513. [Abstract] [Full Text] [PDF]

				K.-P. Chuang, Y.-F. Huang, Y.-L. Hsu, H.-S. Liu, H.-C. Chen, and C.-C. Shieh Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway Blood, December 15, 2004; 104(13): 4046 - 4053. [Abstract] [Full Text] [PDF]

				C. X. Sun, G. P. Downey, F. Zhu, A. L. Y. Koh, H. Thang, and M. Glogauer Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass Blood, December 1, 2004; 104(12): 3758 - 3765. [Abstract] [Full Text] [PDF]

				D. F. Barber, M. Faure, and E. O. Long LFA-1 Contributes an Early Signal for NK Cell Cytotoxicity J. Immunol., September 15, 2004; 173(6): 3653 - 3659. [Abstract] [Full Text] [PDF]