Steinberg Marcos, Adjali Oumeya, Swainson Louise, Merida Peggy, Di Bartolo Vincenzo, Pelletier Ludivine, Taylor Naomi, Noraz Nelly
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.
Blood. 2004 Aug 1;104(3):760-7. doi: 10.1182/blood-2003-12-4314. Epub 2004 Apr 1.
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细胞受体（TCR）的激活会导致Lck/Fyn和ZAP-70/Syk酪氨酸激酶的活化。Lck介导的TCR的CD3-ζ亚基中信号基序（ITAMs）的酪氨酸磷酸化是信号级联转导的初始步骤。然而，ζ磷酸化也由ZAP-70促进，因为TCR诱导的ζ磷酸化在ZAP-70缺陷的T细胞中存在缺陷。我们发现，在原代和转化的T细胞中，通过稳定表达ZAP-70而非Syk可以纠正这种缺陷。事实上，这些蛋白与TCR的偶联存在差异，与Syk相比，ZAP-70与ζ的结合亲和力高5至10倍。低水平的Syk-ζ结合与与TCR偶联的Lck显著减少有关。此外，Lck与ζ的偶联减少与Syk的正调节酪氨酸352残基磷酸化不足相关。因此，ZAP-70促进Lck募集到TCR复合物中并随后使ζ链磷酸化，而Syk则不能。重要的是，ZAP-70的存在正向调节TCR诱导的Syk酪氨酸磷酸化。因此，在胸腺细胞、某些T细胞和B细胞慢性淋巴细胞白血病细胞（它们在其中共表达）中，Syk和ZAP-70之间的相互作用将调节抗原介导的受体信号的幅度。
