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During antigen recognition by T cells, CD4 and the T-cell receptor (TCR)/CD3/zeta complex are thought to interact with the same major histocompatibility complex II molecule in a stable ternary complex. Evidence has suggested that the association of CD4 with TCR/CD3/zeta requires the interaction of the protein tyrosine kinase p56lck with CD4. We have taken a biochemical approach to understand the mechanism by which p56lck and, in particular, its src homology (SH) 2 domain contributes to the association of CD4 with TCR/CD3/zeta during activation. We have previously shown that the p56lck SH2 domain binds directly to tyrosine-phosphorylated ZAP-70. Here we formally demonstrate the in vivo association of p56lck with the homologous protein tyrosine kinases Syk and ZAP-70 after CD3 stimulation of Jurkat cells. A tyrosine-phosphorylated peptide containing the sequence predicted to be optimal for binding to the SH2 domain of src family kinases specifically competes for this association, indicating that tyrosine-phosphorylated ZAP-70 and Syk bind to p56lck by an SH2-mediated interaction. We also show that the same peptide is able to compete for the activation-dependent TCR/CD4 association in Jurkat cells. Moreover, ZAP-70 and CD4 cocap only after CD3 stimulation in human T lymphoblasts. We propose that the interaction of the p56lck SH2 domain with zeta-associated tyrosine-phosphorylated ZAP-70 and/or Syk enables CD4 to associate with antigen-stimulated TCR/CD3/zeta complexes.

Type

Journal article

Journal

J Exp Med

Publication Date

01/06/1995

Volume

181

Pages

1997 - 2006

Keywords

Antigens, CD, CD4 Antigens, Cell Line, Electrophoresis, Polyacrylamide Gel, Enzyme Precursors, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Lymphocyte Activation, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Membrane Proteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein-Tyrosine Kinases, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, Syk Kinase, T-Lymphocytes, Tumor Cells, Cultured, Tyrosine, ZAP-70 Protein-Tyrosine Kinase