The Adapter Protein SLP-76 Mediates “Outside-In” Integrin Signaling and Function in T Cells

Abstract

The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank Taku Kambayashi and Laurie Lenox for critical reading of the manuscript, Yoji Shimizu and Christopher DeNucci and members of the Burkhardt laboratory for technical advice, and Justina Stadanlick for editorial assistance.

J.S.M. is a John Merrill Scholar of the American Society of Nephrology. This work was supported by the American Heart Association (R.G.B.) and the NIH (G.A.K., D.A.H., and T.B.).