The adapter protein SLP-76 mediates "outside-in" integrin signaling and function in T cells.
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.
Baker
R G
RG
Abramson Family Cancer Research Institute, University of Pennsylvania, 415 BRB/421 Curie Blvd., Philadelphia, PA 19104, USA.
Hsu
C J
CJ
Lee
D
D
Jordan
M S
MS
Maltzman
J S
JS
Hammer
D A
DA
Baumgart
T
T
Koretzky
G A
GA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C106957:FYB1 protein, human; D016023:Integrins; C110810:LAT protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D020794:Receptor Protein-Tyrosine Kinases; D020827:rap1 GTP-Binding Proteins