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Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.

Original publication

DOI

10.1084/jem.20060650

Type

Journal article

Journal

J Exp Med

Publication Date

30/10/2006

Volume

203

Pages

2509 - 2518

Keywords

Adaptor Proteins, Signal Transducing, Cell Line, Tumor, DNA-Binding Proteins, Down-Regulation, Feedback, Physiological, GRB2 Adaptor Protein, Humans, Inositol Polyphosphate 5-Phosphatases, Jurkat Cells, Ligands, Lymphocyte Activation, Membrane Proteins, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoproteins, Phosphoric Monoester Hydrolases, Phosphorylation, RNA-Binding Proteins, Receptor-CD3 Complex, Antigen, T-Cell, Signal Transduction, Tyrosine