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Molecular and Cellular Biology, October 2006, p. 7130-7144, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00331-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The ADAP/SKAP55 Signaling Module Regulates T-Cell Receptor-Mediated Integrin Activation through Plasma Membrane Targeting of Rap1{dagger}

Stefanie Kliche,1* Dennis Breitling,1 Mauro Togni,1 Rico Pusch,1 Katja Heuer,2 Xiaoqian Wang,1 Christian Freund,2 Ana Kasirer-Friede,3 Gael Menasche,4 Gary A. Koretzky,4 and Burkhart Schraven1

Institute of Immunology, Otto von Guericke University, 39120 Magdeburg, Germany,1 Protein Engineering Group, Forschungsinstitut für Molekulare Pharmakologie an der Freien Universität Berlin, 13125 Berlin, Germany,2 Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093,3 Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191044

Received 23 February 2006/ Returned for modification 6 May 2006/ Accepted 15 July 2006

Adhesion of T cells after stimulation of the T-cell receptor (TCR) is mediated via signaling processes that have collectively been termed inside-out signaling. The molecular basis for inside-out signaling is not yet completely understood. Here, we show that a signaling module comprising the cytosolic adapter proteins ADAP and SKAP55 is involved in TCR-mediated inside-out signaling and, moreover, that the interaction between ADAP and SKAP55 is mandatory for integrin activation. Disruption of the ADAP/SKAP55 module leads to displacement of the small GTPase Rap1 from the plasma membrane without influencing its GTPase activity. These findings suggest that the ADAP/SKAP55 complex serves to recruit activated Rap1 to the plasma membrane. In line with this hypothesis is the finding that membrane targeting of the ADAP/SKAP55 module induces T-cell adhesion in the absence of TCR-mediated stimuli. However, it appears as if the ADAP/SKAP55 module can exert its signaling function outside of the classical raft fraction of the cell membrane.

* Corresponding author. Mailing address: Institute of Immunology, Otto von Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. Phone: 49-391-67-15855. Fax: 49-391-67-15865. E-mail: stefanie.kliche{at}medizin.uni-magdeburg.de.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2006, p. 7130-7144, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.00331-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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