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Originally published In Press as doi:10.1074/jbc.M102896200 on August 6, 2001

J. Biol. Chem., Vol. 276, Issue 44, 40518-40527, November 2, 2001
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Rho and Rho-associated Kinase Modulate the Tyrosine Kinase PYK2 in T-cells through Regulation of the Activity of the Integrin LFA-1*

José Luis Rodríguez-FernándezDagger §, Lorena Sánchez-MartínDagger ||, Mercedes Rey**, Miguel Vicente-Manzanares**, Shuh NarumiyaDagger Dagger , Joaquín Teixidó§§, Francisco Sánchez-Madrid**, and Carlos CabañasDagger ¶¶

From the Dagger  Instituto de Farmacología y Toxicología CSIC, Facultad de Medicina, Universidad Complutense, 28040 Madrid, ** Servicio de Inmunología, Hospital de la Princesa, 28006 Madrid, Spain, the Dagger Dagger  Department of Pharmacology, Kyoto University, Faculty of Medicine, Kyoto 606, Japan, and §§ Departamento de Inmunología, Centro de Investigaciones Biológicas CSIC, Velázquez 144, 28006 Madrid, Spain

We have examined the role of the small GTPase Rho and its downstream effector, the Rho-associated kinase (ROCK), in the control of the adhesive and signaling function of the lymphocyte function-associated antigen-1 (LFA-1) integrin in human T-lymphocytes. Inhibition of Rho (either by treatment with C3-exoenzyme or transfection with a dominant-negative form of Rho (N19Rho)) or ROCK (by treatment with Y-27632) results in the following: (a) partial disorganization and aggregation of cortical filamentous actin (F-actin); (b) induction of LFA-1-mediated cellular adhesion to the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1) through a mechanism involving clustering of LFA-1 molecules, rather than alterations in the level of expression or in the affinity state of this integrin; and (c) induction of cellular polarization and activation of the tyrosine kinase PYK2. Transfection of T-cells with a constitutively active form of Rho (V14Rho) blocks the clustering of LFA-1 on the membrane and the LFA-1-mediated activation of PYK2. Importantly, the activation of PYK2 caused by inhibition of Rho or ROCK takes place only when the T-cells are plated onto ICAM-1 but not when they are either prevented from interacting with ICAM-1 with anti-LFA-1 blocking antibodies or when they are plated on the nonspecific poly-L-lysine substrate. These results indicate that the small GTPase Rho regulates the tyrosine kinase PYK2 in T-cells through the F-actin-mediated control of the activity of the integrin LFA-1. These findings represent a novel paradigm for the regulation of the activity of a cytoplasmic tyrosine kinase by the small GTPase Rho.

* This work was supported in part by Grants SAF 98/0080 from Comisión Interministerial de Ciencia y Tecnología, 08.1/0015/1997 and 08.3/0010.2/1999 from "Comunidad de Madrid" (to C. C.), Grants SAF99-0034-C02-01 and 2FD97-0680-C02-02 from the Ministerio de Educación y Cultura, by QLRT-1999-01036 from the European Community (to F. S.-M.), and Grant SAF 99/0057 from CICYT (to J. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a "Contrato de Reincorporación" associated with Grants DGICYT PB94-0231 and CICYT SAF98/0080 from the "Ministerio Español de Educación y Cultura." To whom correspondence regarding PYK2 should be addressed. Present address: Laboratorio de Immunooncología, Hospital Gregorio Maranón, Doctor Esquerdo 46, 28007 Madrid, Spain.

Both authors contributed equally to this work.

|| Recipient of a fellowship "Incorporación de Técnicos a Equipos de Investigación" from "Comunidad de Madrid."

¶¶ To whom correspondence should be addressed: Instituto de Farmacología y Toxicología CSIC, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain. Tel.: 34 91 3941444; Fax: 34 91 3941470; E-mail: cacabagu@eucmax.sim.ucm.es.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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