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Blood, 1 August 2004, Vol. 104, No. 3, pp. 760-767.
Prepublished online as a Blood First Edition Paper on April 1, 2004; DOI 10.1182/blood-2003-12-4314.
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IMMUNOBIOLOGY
T-cell receptor–induced phosphorylation of the  chain is efficiently promoted by ZAP-70 but not Syk
Marcos Steinberg,
Oumeya Adjali,
Louise Swainson,
Peggy Merida,
Vincenzo Di Bartolo,
Ludivine Pelletier,
Naomi Taylor, and
Nelly Noraz
From the Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherches (UMR) 5535/Institut Fédératif de Recherche (IFR) 122, F-34293 Montpellier Cedex 5; and the Laboratory of Molecular Immunology, Institut Pasteur, 75724 Paris Cedex 15, France.
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- subunits of the TCR is an initial step in the transduction of signaling cascades. However, phosphorylation is also promoted by ZAP-70, as TCR-induced 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 as compared to Syk. Low-level Syk- binding is associated with significantly less Lck coupled to the TCR. Moreover, diminished coupling of Lck to correlates with a poor phosphorylation of the positive regulatory tyr352 residue of Syk. Thus, recruitment of Lck into the TCR complex with subsequent 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.
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