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.

Shen Dong (1) , Béatrice Corre (1) , Elodie Foulon (1) , E. Dufour (1) , A. Veillette (2) , Oreste Acuto (1) , Frédérique Michel (1)

1 Immunologie Moléculaire
2 McGill University = Université McGill [Montréal, Canada]

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.

Domains: Immunology

Shen Dong, Béatrice Corre, Elodie Foulon, E. Dufour, A. Veillette, et al.. 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.. Journal of Experimental Medicine, 2006, 203 (11), pp.2509-18. ⟨10.1084/jem.20060650⟩. ⟨pasteur-00162042⟩