T-cell receptor-induced phosphorylation of the zeta chain is efficiently promoted by ZAP-70 but not Syk.
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.
Steinberg
Marcos
M
Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique Unité de Recherches 5535/Institut Fédératife de Recherche, F-34293 Montpellier 5, France.
Adjali
Oumeya
O
Swainson
Louise
L
Merida
Peggy
P
Di Bartolo
Vincenzo
V
Pelletier
Ludivine
L
Taylor
Naomi
N
Noraz
Nelly
N
D001402:B-Lymphocytes / Q000276:immunology; D004792:Enzyme Precursors / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D010766:Phosphorylation; D021122:Protein Subunits / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human