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Molecular and Cellular Biology, June 2007, p. 4070-4081, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.02011-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RIAM Links the ADAP/SKAP-55 Signaling Module to Rap1, Facilitating T-Cell-Receptor-Mediated Integrin Activation

Gaël Ménasché,^1, Stefanie Kliche,^2, Emily J. H. Chen,¹ Theresia E. B. Stradal,³ Burkhart Schraven,² and Gary Koretzky^1,4*

Signal of Transduction Program, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,¹ Institute of Immunology, Otto von Guericke University, 39120 Magdeburg, Germany,² Signaling and Motility Group, Helmholtz Center for Infection Research (HZI), 38124 Braunschweig, Germany,³ Department of Pathology and Laboratory Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104⁴

Received 26 October 2006/ Returned for modification 8 December 2006/ Accepted 20 March 2007

One outcome of T-cell receptor (TCR) signaling is increased affinity and avidity of integrins for their ligands. This occurs through a process known as inside-out signaling, which has been shown to require several molecular components including the adapter proteins ADAP (adhesion and degranulation-promoting adapter protein) and SKAP-55 (55-kDa src kinase-associated phosphoprotein) and the small GTPase Rap1. Herein, we provide evidence linking ADAP and SKAP-55 to RIAM, a recently described adapter protein that binds selectively to active Rap1. We identified RIAM as a key component linking the ADAP/SKAP-55 module to the small GTPase Rap1, facilitating TCR-mediated integrin activation. We show that RIAM constitutively interacts with SKAP-55 in both a heterologous transfection system and primary T cells and map the region essential for this interaction. Additionally, we find that the SKAP-55/RIAM complex is essential both for TCR-mediated adhesion and for efficient conjugate formation between T cells and antigen-presenting cells. Mechanistic studies revealed that the ADAP/SKAP-55 module relocalized RIAM and Rap1 to the plasma membrane following TCR activation to facilitate integrin activation. These results describe for the first time a link between ADAP/SKAP-55 and the Rap1/RIAM complex and provide a potential new mechanism for TCR-mediated integrin activation.

Published ahead of print on 2 April 2007.

These authors contributed equally to this work.