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Molecular and Cellular Biology, October 2009, p. 5578-5589, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00283-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Adapter Protein SLP-76 Mediates "Outside-In" Integrin Signaling and Function in T Cells{triangledown} ,{dagger}

R. G. Baker,1 C. J. Hsu,2 D. Lee,3 M. S. Jordan,1,5 J. S. Maltzman,4 D. A. Hammer,3 T. Baumgart,2 and G. A. Koretzky1,4,5*

Abramson Family Cancer Research Institute,1 Department of Chemistry,2 Department of Bioengineering,3 Department of Medicine,4 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania5

Received 3 March 2009/ Returned for modification 29 April 2009/ Accepted 30 July 2009

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.

* Corresponding author. Mailing address: Abramson Family Cancer Research Institute, University of Pennsylvania, 415 BRB/421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5522. Fax: (215) 746-5525. E-mail: koretzky{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 10 August 2009.

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

Molecular and Cellular Biology, October 2009, p. 5578-5589, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00283-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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