ZAP-70 is a member of a distinct family of cytoplasmic tyrosine kinases involved in signal transduction from the antigen receptors. The family currently consists of ZAP-70, which is found in T lymphocytes and natural killer (NK) cells and Syk, which is most highly expressed in B lymphocytes and platelets.<sup>12 Chu D.H., Morita C.T., Weiss A. The Syk family of protein tyrosine kinases in T-cell activation and development Immunol Rev 1998 ;  165 : 167  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> ZAP-70 was isolated initially as an ATP-binding phosphoprotein associating with a component of the T-cell receptor (TCR) signaling complex, CD3ζ, after TCR stimulation.<sup>9 Chan A.C., Iwashima M., Turck C.W. , y al. ZAP-70: A 70-kd protein-tyrosine kinase that associates with the TCR ζ chain Cell 1992 ;  71 : 649  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 87 Wange R.L., Kong A.N., Samelson L.E. A tyrosine-phosphorylated 70-kDa protein binds a photoaffinity analogue of ATP and associates with both the ζ chain and CD3 components of the activated T-cell antigen receptor J Biol Chem 1992 ;  267 : 11685

Haga clic aquí para ir a la sección de Referencias, 90 Weiss A., Chan A.C., Iwashima M. , y al. Regulation of protein tyrosine kinase activation by the T-cell antigen receptor ζ chain Cold Spring Harb Symp Quant Biol 1992 ;  57 : 107

Haga clic aquí para ir a la sección de Referencias</sup> ZAP-70 has a single protein tyrosine kinase catalytic domain and tandem SH2 domains responsible for binding to the CD3ζ receptor chain. This structure is shared by the closely related Syk kinase.<sup>12 Chu D.H., Morita C.T., Weiss A. The Syk family of protein tyrosine kinases in T-cell activation and development Immunol Rev 1998 ;  165 : 167  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> Both kinases also have multiple tyrosine residues predicted to form recognition sites for SH2 domains. ZAP-70 is expressed from an extremely early point in T-cell differentiation, and is present in all the major thymocyte subpopulations.<sup>11 Chan A.C., van Oers N.S., Tran A. , y al. Differential expression of ZAP-70 and Syk protein tyrosine kinases and the role of this family of protein tyrosine kinases in TCR signaling J Immunol 1994 ;  152 : 4758

Haga clic aquí para ir a la sección de Referencias</sup> Expression does not seem to be inducible, but remains constant throughout the developmental process. A single gene on chromosome 2q12 encodes the human ZAP-70 kinase.<sup>38 Ku G., Malissen B., Mattei M.G. Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans Immunogenetics 1994 ;  40 : 300

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Although playing a critical role in T-cell antigen receptor signaling, the activation of ZAP-70 is not the primary event following TCR ligation. Rather, ZAP-70 activation seems to lie downstream of members of the src tyrosine kinase family, and, as a result of their activity, ZAP-70 is activated.<sup>82 van Oers N.S., Killeen N., Weiss A. Lck regulates the tyrosine phosphorylation of the T-cell receptor subunits and ZAP-70 in murine thymocytes J Exp Med 1996 ;  183 : 1053

Haga clic aquí para ir a la sección de Referencias, 89 Weil R., Cloutier J.F., Fournel M. , y al. Regulation of ZAP-70 by Src family tyrosine protein kinases in an antigen-specific T-cell line J Biol Chem 1995 ;  270 : 2791

Haga clic aquí para ir a la sección de Referencias</sup> This is, in part, because of phosphorylation of CD3ζ by the src kinases, primarily p56lck, and, in part, because of phosphorylation of ZAP-70 itself. On TCR stimulation, ZAP-70 rapidly moves from the cytoplasm to the plasma membrane, binding to the CD3ζ chain of the TCR complex. It then is tyrosine phosphorylated rapidly and its kinase domain is activated. Various signal transduction proteins become associated with ZAP-70, some of which are substrates for its kinase domain and others that modify and regulate its activity. Localization to the plasma membrane plays an important role in ZAP-70 activation, as artificial targeting to the membrane results in ZAP-70 phosphorylation and activation of the downstream ras/MAPK and Ca²⁺/calcineurin pathways.<sup>25 Graef I.A., Holsinger L.J., Diver S. , y al. Proximity and orientation underlie signaling by the nonreceptor tyrosine kinase ZAP-70 EMBO J 1997 ;  16 : 5618

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