T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2.
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.
Dong
Shen
S
Molecular Immunology Unit, Department of Immunology, Institut Pasteur, 75724 Paris Cedex 15, France.
Corre
Béatrice
B
Foulon
Eliane
E
Dufour
Evelyne
E
Veillette
André
A
Acuto
Oreste
O
Michel
Frédérique
F
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D051380:GRB2 Adaptor Protein / Q000502:physiology*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C115089:DOK2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C110810:LAT protein, human; D008024:Ligands; D008565:Membrane Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014443:Tyrosine; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases