ZAP-70

ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 (70 is the molecular weight in kDa). The protein is a member in the protein-tyrosine kinase family. ZAP-70 is normally expressed in T cells and natural killer cells and has a critical role in the initiation of T-cell signaling.

Clinical significance

ZAP-70 in B cells is used as a prognostic marker in identifying different forms of chronic lymphocytic leukemia (CLL).

ZAP70 deficiency results in a form of immune deficiency.

Function

T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (e.g. macrophages, dendritic cells and B cells). Upon this activation, the tyrosine kinase Lck becomes activated and phosphorylates the intracellular portions of the CD3 complex (called ITAMs). The most important member of the CD3 family is CD3-zeta to which ZAP-70 binds (hence the abbreviation). The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta, which positions ZAP-70 to phosphorylate the transmembrane protein LAT (Linker of Activated T cells). Phosphorylated LAT in turn serves as a docking site to which a number of signaling proteins bind. The final outcome of T cell activation is the transcription of several gene products which allow the T cells to differentiate, proliferate and secrete a number of cytokines.

ee also

* Lck
* Syk

Further reading

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*PBB_Further_reading
citations =
*cite journal | author=Orchard J, Ibbotson R, Best G, "et al." |title=ZAP-70 in B cell malignancies. |journal=Leuk. Lymphoma |volume=46 |issue= 12 |pages= 1689–98 |year= 2006 |pmid= 16263570 |doi= 10.1080/09638280500260079
*cite journal | author=Hamblin AD, Hamblin TJ |title=Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia. |journal=Expert Opin. Ther. Targets |volume=9 |issue= 6 |pages= 1165–78 |year= 2006 |pmid= 16300468 |doi= 10.1517/14728222.9.6.1165
*cite journal | author=Chan AC, Iwashima M, Turck CW, Weiss A |title=ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. |journal=Cell |volume=71 |issue= 4 |pages= 649–62 |year= 1992 |pmid= 1423621 |doi=
*cite journal | author=Goldman F, Jensen WA, Johnson GL, "et al." |title=gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation. |journal=J. Immunol. |volume=153 |issue= 7 |pages= 2905–17 |year= 1994 |pmid= 7522245 |doi=
*cite journal | author=Isakov N, Wange RL, Burgess WH, "et al." |title=ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. |journal=J. Exp. Med. |volume=181 |issue= 1 |pages= 375–80 |year= 1995 |pmid= 7528772 |doi=
*cite journal | author=Nel AE, Gupta S, Lee L, "et al." |title=Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. |journal=J. Biol. Chem. |volume=270 |issue= 31 |pages= 18428–36 |year= 1995 |pmid= 7629168 |doi=
*cite journal | author=Negishi I, Motoyama N, Nakayama K, "et al." |title=Essential role for ZAP-70 in both positive and negative selection of thymocytes. |journal=Nature |volume=376 |issue= 6539 |pages= 435–8 |year= 1995 |pmid= 7630421 |doi= 10.1038/376435a0
*cite journal | author=Mustelin T, Williams S, Tailor P, "et al." |title=Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase. |journal=Eur. J. Immunol. |volume=25 |issue= 4 |pages= 942–6 |year= 1995 |pmid= 7737297 |doi=
*cite journal | author=Neumeister EN, Zhu Y, Richard S, "et al." |title=Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins. |journal=Mol. Cell. Biol. |volume=15 |issue= 6 |pages= 3171–8 |year= 1995 |pmid= 7760813 |doi=
*cite journal | author=Katzav S, Sutherland M, Packham G, "et al." |title=The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav. |journal=J. Biol. Chem. |volume=269 |issue= 51 |pages= 32579–85 |year= 1995 |pmid= 7798261 |doi=
*cite journal | author=Schumann G, Dasgupta JD |title=Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif. |journal=Int. Immunol. |volume=6 |issue= 9 |pages= 1383–92 |year= 1995 |pmid= 7819147 |doi=
*cite journal | author=Watts JD, Affolter M, Krebs DL, "et al." |title=Identification by electrospray ionization mass spectrometry of the sites of tyrosine phosphorylation induced in activated Jurkat T cells on the protein tyrosine kinase ZAP-70. |journal=J. Biol. Chem. |volume=269 |issue= 47 |pages= 29520–9 |year= 1994 |pmid= 7961936 |doi=
*cite journal | author=Ku G, Malissen B, Mattei MG |title=Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans. |journal=Immunogenetics |volume=40 |issue= 4 |pages= 300–2 |year= 1994 |pmid= 8082894 |doi=
*cite journal | author=Chan AC, van Oers NS, Tran A, "et al." |title=Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. |journal=J. Immunol. |volume=152 |issue= 10 |pages= 4758–66 |year= 1994 |pmid= 8176201 |doi=
*cite journal | author=Elder ME, Lin D, Clever J, "et al." |title=Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. |journal=Science |volume=264 |issue= 5165 |pages= 1596–9 |year= 1994 |pmid= 8202712 |doi=
*cite journal | author=Chan AC, Kadlecek TA, Elder ME, "et al." |title=ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. |journal=Science |volume=264 |issue= 5165 |pages= 1599–601 |year= 1994 |pmid= 8202713 |doi=
*cite journal | author=Wange RL, Malek SN, Desiderio S, Samelson LE |title=Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells. |journal=J. Biol. Chem. |volume=268 |issue= 26 |pages= 19797–801 |year= 1993 |pmid= 8366117 |doi=
*cite journal | author=Huby RD, Carlile GW, Ley SC |title=Interactions between the protein-tyrosine kinase ZAP-70, the proto-oncoprotein Vav, and tubulin in Jurkat T cells. |journal=J. Biol. Chem. |volume=270 |issue= 51 |pages= 30241–4 |year= 1996 |pmid= 8530437 |doi=
*cite journal | author=Plas DR, Johnson R, Pingel JT, "et al." |title=Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. |journal=Science |volume=272 |issue= 5265 |pages= 1173–6 |year= 1996 |pmid= 8638162 |doi=
*cite journal | author=Wardenburg JB, Fu C, Jackman JK, "et al." |title=Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. |journal=J. Biol. Chem. |volume=271 |issue= 33 |pages= 19641–4 |year= 1996 |pmid= 8702662 |doi=

External links

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