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Overview
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Background
ZAP-70; ζ-associated protein of 70 kDa tyrosine kinase, was identified as a tyrosine phosphoprotein that associates with TCR ζ subunit and undergoes tyrosine phosphorylation following TCR stimulation. ZAP-70 is a Syk family tyrosine kinase primarily expressed in T and NK cells that plays an essential role in signaling through the TCR. TCR-mediated activation of T cells is crucial to the immune response. In humans, ZAP-70 gene mutations resulting in lower ZAP-70 protein expression levels or expression of catalytically inactive ZAP-70 proteins, have been identified. ZAP-70 deficiency results in the absence of mature CD8+ T cells and the prevention of TCR-mediated activation of CD4+ T cells, and it can lead to severe combined immunodeficiency. In patients with chronic lymphocytic leukemia (B-CLL), ZAP-70 expression on B cell was shown to be correlated with disease progression and survival. ZAP-70 contains two N-terminal SH2 domains (Src homology domain 2) and a C-terminal kinase domain. During T cell activation, the binding of ZAP-70 SH2 domains to the phosphorylated ζ subunit on the activated TCR complex causes a colocalization with the Lck tyrosine kinase that phosphorylates ZAP-70 on Tyr493 in the activation loop. ZAP-70 autophosphorylates multiple tyrosines in the region between the SH2 domains and the kinase domain, including the binding sites for additional SH2-containing signaling proteins such as SLP76, LAT, Lck, PLCγ1, Vav, Shc, Ras-GAP, and Abl. ZAP-70-mediated activation of these downstream effectors leads to the release of intracellular calcium stores, and the transcription of interleukin-2 and other genes important for an immune response.
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Overview