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PMID: 17043143 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

The Journal of experimental medicine ·Vol. 203 ·No. 11 ·2006-10-30 ·Pages 2509-18

Dong S, Corre B, Foulon E, Dufour E, Veillette A, Acuto O, Michel F

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/biosynthesis,metabolism,physiology Cell Line, Tumor DNA-Binding Proteins/physiology Down-Regulation/immunology Feedback, Physiological/immunology GRB2 Adaptor Protein/physiology Humans Inositol Polyphosphate 5-Phosphatases Jurkat Cells Ligands Lymphocyte Activation Membrane Proteins/biosynthesis,metabolism,physiology Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases Phosphoproteins/physiology Phosphoric Monoester Hydrolases/physiology Phosphorylation RNA-Binding Proteins/physiology Receptor-CD3 Complex, Antigen, T-Cell/metabolism,physiology Signal Transduction/immunology Tyrosine/metabolism
Chemicals
Adaptor Proteins, Signal Transducing DNA-Binding Proteins DOK1 protein, human DOK2 protein, human GRB2 Adaptor Protein GRB2 protein, human LAT protein, human Ligands Membrane Proteins Phosphoproteins RNA-Binding Proteins Receptor-CD3 Complex, Antigen, T-Cell Tyrosine Phosphoric Monoester Hydrolases Inositol Polyphosphate 5-Phosphatases INPP5D protein, human Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dong Shen
Molecular Immunology Unit, Department of Immunology, Institut Pasteur, 75724 Paris Cedex 15, France.
Corre Béatrice
Foulon Eliane
Dufour Evelyne
Veillette André
Acuto Oreste
Michel Frédérique
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20060650
Published
2006-10-30
Epub
2006-00-16
Pages
2509-18
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118126
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20060650 PMC Full Text View journal details
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