The Journal of Experimental Medicine
StemCell Technologies
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Published online 16 October 2006 doi:10.1084/jem.20060650
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 11, 2509-2518
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ARTICLE

 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 Dong1, Béatrice Corre1, Eliane Foulon1, Evelyne Dufour1, André Veillette2, Oreste Acuto1, and Frédérique Michel1

1 Molecular Immunology Unit, Department of Immunology, Institut Pasteur, 75724 Paris Cedex 15, France
2 McGill Cancer Centre and Departments of Biochemistry, Oncology and Medicine McGill University, Montreal, Quebec, H3G 1Y6, Canada

CORRESPONDENCE Frédérique Michel: fmichel{at}pasteur.fr

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.

Abbreviations used: BCR, B lymphocyte antigen receptor; CML, chronic myelogenous leukemia; Dok, downstream of kinase; ERK, extracellular signal-regulated kinase; LAT, linker for activation of T cells; PH, pleckstrin homology; PI, phosphatidylinositol; PTEN, phosphatase and tensin homologue deleted in chromosome 10; SH, Src homology; SHIP, SH2 domain-containing inositol polyphosphate 5'-phosphatase; SAg, superantigen; si, small interfering.

S. Dong and B. Corre contributed equally to this work.

F. Michel's present address is Cytokine Signaling Unit, Institut Pasteur, Paris, 75015 France.

O. Acuto's present address is Sir William Dunn School of Pathology, Oxford OX1 3RE, UK.


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