The hematopoietic-specific adaptor protein Gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors

Background: The adaptor protein Gads is a Grb2-related protein originally i dentified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc. Gads protein expression is restricted to h ematopoietic tissues and cell lines, Gads contains a Src homology 2 (SH2) d omain, which has previously been shown to have a similar binding specificit y to that of Grb2. Gads also possesses two SH3 domains, but these have a di stinct binding specificity to those of Grb2, as Gads does not bind to known Grb2 SH3 domain targets. Here, we investigated whether Gads is involved in T-cell signaling. Results: We found that Gads is highly expressed in T cells and that the SLP -76 adaptor protein is a major Gads-associated protein in vivo. The constit utive interaction between Gads and SLP-76 was mediated by the carboxy-termi nal SH3 domain of Gads and a 20 amino-acid proline-rich region in SLP-76. G ads also coimmunoprecipitated the tyrosine-phosphorylated form of the linke r for activated T cells (LAT) adaptor protein following cross-linking of th e T-cell receptor; this interaction was mediated by the Gads SH2 domain. Ov erexpression of Gads and SLP-76 resulted in a synergistic augmentation of T -cell signaling, as measured by activation of nuclear factor of activated T cells (NFAT), and this cooperation required a functional Gads SH2 domain. Conclusions: These results demonstrate that Gads plays an important role in T-cell signaling via its association with SLP-76 and LAT. Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby couplin g membrane-proximal events to downstream signaling pathways.