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

Abstract

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.

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

This work was supported by the Deutsche Forschungsgemeinschaft grants KL1292/5-1 and GRK1167 as well as by grants from the U.S. National Institutes of Health.

We thank C. Merten, A. Nehring, J. Hoppe, and P. Glintschel for excellent technical assistance. We thank Vaclav Horejsi for providing monoclonal antibodies.