Engagement of the T-cell receptor (TCR) results in the activation of Lck/Fyn and ZAP-70/Syk tyrosine kinases. Lck-mediated tyrosine phosphorylation of signaling motifs (ITAMs) in the CD3-zeta subunits of the TCR is an initial step in the transduction of signaling cascades. However, zeta phosphorylation is also promoted by ZAP-70, as TCR-induced zeta phosphorylation is defective in ZAP-70-deficient T cells. We show that this defect is corrected by stable expression of ZAP-70, but not Syk, in primary and transformed T cells. Indeed, these proteins are differentially coupled to the TCR with a 5- to 10-fold higher association of ZAP-70 with zeta as compared to Syk. Low-level Syk-zeta binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to zeta correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent zeta chain phosphorylation is promoted by ZAP-70 but not Syk. Importantly, the presence of ZAP-70 positively regulates the TCR-induced tyrosine phosphorylation of Syk. The interplay between Syk and ZAP-70 in thymocytes, certain T cells, and B-chronic lymphocytic leukemia cells, in which they are coexpressed, will therefore modulate the amplitude of antigen-mediated receptor signaling.
T-cell receptor-induced phosphorylation of the zeta chain is efficiently promoted by ZAP-70 but not Syk
Steinberg, M.; Adjali, O.; Swainson, L.; Merida, P.; Di Bartolo, V.; Pelletier, L.; Taylor, N.; Noraz, N.
2004-08-01 / vol 104 / pages 760-7
Humans; Phosphorylation; ZAP-70 Protein-Tyrosine Kinase; B-Lymphocytes/immunology; Enzyme Precursors/*immunology; Intracellular Signaling Peptides and Proteins; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell/immunology; Membrane Proteins/*immunology; Protein Subunits/immunology; Protein-Tyrosine Kinases/*immunology; Receptors, Antigen, T-Cell/*immunology; Signal Transduction/immunology; T-Lymphocytes/*immunology; Thymus Gland/immunology