The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

ZAP70  -  zeta-chain (TCR) associated protein kinase...

Homo sapiens

Synonyms: 70 kDa zeta-chain associated protein, SRK, STCD, STD, Syk-related tyrosine kinase, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of ZAP70


High impact information on ZAP70


Chemical compound and disease context of ZAP70


Biological context of ZAP70

  • Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor kappaB pathway without inducing phosphorylation of either TCRzeta or ZAP70 [12].
  • Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the adenosine triphosphate (ATP) binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib [13].
  • Consistent with this observation, pp55 selectively binds to isolated SH2 domains of Lck, Lyn, Src, and Fyn but not to the SH2 domains of ZAP70, Syk, Shc, SLP-76, Grb2, phosphatidylinositol 3-kinase, and c-abl in vitro [14].
  • Previous studies have demonstrated that lack or diminished activation of ZAP70 is involved in the induction of anergy or apoptosis in T cells [15].
  • The tyrosine-phosphorylated ZAP70 kinase exhibits a particular phenotype with low affinities for proteins at 21, 40, 60, and 120 kDa, proteins normally co-precipitated with ZAP70 after TCR/CD3 stimulation [15].

Anatomical context of ZAP70

  • Since tyrosine phosphorylated pp29/30 selectively interacts with the Src homology type 2 domains (SHZ) of the protein tyrosine kinases p56lck and p59fyn but not ZAP70 the present data suggest that pp29/30 represents a novel signaling receptor associated phosphoprotein likely involved in the activation of human T lymphocytes and NK cells [16].
  • Finally, ZAP70 was not concentrated near the plasma membrane in the apoptosis-deficient cells [17].
  • In contrast to untreated Th2 cells, anergized Th2 cells failed to respond to anti-CD3 mAb with either increased tyrosine kinase activity or increased levels of tyrosine phosphorylation of p56(lck) or ZAP70 [18].
  • CA125 did not reduce proliferation or induce apoptosis of NK cells and alter the expression of p56lck, phospholipase Cgamma1, ZAP70, or CD3zeta [19].
  • Using ZAP-70-deficient T cells expressing zeta-GFP, we show that ZAP-70 signaling drives the TCR-dependent reorientation of the microtubule-organizing center thus leading to relocation of a zeta-GFP(+) intracellular compartment close to the APC [20].

Associations of ZAP70 with chemical compounds

  • Substrates for the ZAP70/Syk tyrosine kinases are important, but 'missing', links in this process [21].
  • Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR [13].
  • COS cell-expressed glutathione S-transferase-SHP-1L can dephosphorylate tyrosine-phosphorylated ZAP70 [22].
  • Indeed, overexpression in Jurkat cells and in a murine T cell hybridoma of a ZAP-70 mutant in which Tyr319 was replaced by phenylalanine (ZAP-70-Y319F) dramatically impaired anti-TCR-induced activation of the nuclear factor of activated T cells and interleukin-2 production, respectively [23].
  • Treatment with Hsp90 inhibitors such as 17-AAG and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) induced ZAP-70 degradation and apoptosis in CLL cells but not in T cells, and also impaired B-cell receptor signaling in leukemia cells [8].
  • Two tyrosine residues in the SH2-kinase linker that activate ZAP-70 when phosphorylated are involved in aromatic-aromatic interactions that connect the linker to the kinase domain [24].

Physical interactions of ZAP70


Enzymatic interactions of ZAP70

  • Moreover, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cellular systems [29].
  • ZAP-70 phosphorylated HIP-55 at Tyr-334 and Tyr-344 in vitro and in vivo, and the HIP-55 mutant (Y334F/Y344F) was not tyrosine-phosphorylated in stimulated T cells [25].
  • We show in the present report that ZAP-70 is insignificantly tyrosine phosphorylated and recruited to CD3 after CD2 stimulation in Jurkat T cells [27].
  • We also show that recombinant forms of both p56(lck) and ZAP-70 phosphorylate Sam68 in vitro [30].
  • The activity of baculoviral expressed ZAP-70 was up-regulated 10-fold when ZAP-70 was co-infected and phosphorylated by the src family PTK, lck [31].

Regulatory relationships of ZAP70

  • Phosphorylation of SLP-76 is diminished in T cells that express a catalytically inactive ZAP-70 [29].
  • Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine [32].
  • Treatment of Jurkat T cells with TNF activated Syk kinase but not ZAP70, another member of Syk kinase family, and the optimum activation occurred at 10 s and with 1 nM TNF [33].
  • The aim of the present study was to identify the signaling pathways that follow CD44-triggered ZAP-70 phosphorylation and the molecular mechanisms underlying the CD44 interaction with p56(lck) [34].
  • A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T cells [30].

Other interactions of ZAP70

  • Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling [35].
  • We observed that SLAP is expressed in T cells, and upon TCR activation, SLAP interacts with ZAP-70, Syk, LAT, and TCRzeta chain in Jurkat T cells [36].
  • In contrast, CLL B cells that had mutated immunoglobulin variable V genes, or that had low-level expression of CD38, generally did not express detectable amounts of ZAP-70 protein [37].
  • Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration [38].
  • Here we show that the zeta-associated protein 70 (ZAP-70), a key element in TCR signaling, is required for CXCR4 signal transduction [38].

Analytical, diagnostic and therapeutic context of ZAP70


  1. Defective expression of the T-cell receptor-CD3 zeta chain in T-cell acute lymphoblastic leukaemia. Torelli, G.F., Paolini, R., Tatarelli, C., Soriani, A., Vitale, A., Guarini, A., Santoni, A., Foa, R. Br. J. Haematol. (2003) [Pubmed]
  2. Distribution and ZAP-70 expression of WHO lymphoma categories in Shanxi, China: a review of 447 cases using a tissue microarray technique. Wang, J., Young, L., Win, W., Taylor, C.R. Appl. Immunohistochem. Mol. Morphol. (2005) [Pubmed]
  3. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Chen, L., Apgar, J., Huynh, L., Dicker, F., Giago-McGahan, T., Rassenti, L., Weiss, A., Kipps, T.J. Blood (2005) [Pubmed]
  4. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Gobessi, S., Laurenti, L., Longo, P.G., Sica, S., Leone, G., Efremov, D.G. Blood (2007) [Pubmed]
  5. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Chan, A.C., Desai, D.M., Weiss, A. Annu. Rev. Immunol. (1994) [Pubmed]
  6. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R.P., Samelson, L.E. Cell (1998) [Pubmed]
  7. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Chan, A.C., Iwashima, M., Turck, C.W., Weiss, A. Cell (1992) [Pubmed]
  8. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Castro, J.E., Prada, C.E., Loria, O., Kamal, A., Chen, L., Burrows, F.J., Kipps, T.J. Blood (2005) [Pubmed]
  9. Correlation of ZAP-70 expression in B cell leukemias to the ex vivo response to a combination of fludarabine/genistein. Mansour, A., Chang, V.T., Srinivas, S., Harrison, J., Raveche, E. Cancer Immunol. Immunother. (2007) [Pubmed]
  10. The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP-70-negative chronic lymphocytic leukemia. Del Poeta, G., Del Principe, M.I., Consalvo, M.A., Maurillo, L., Buccisano, F., Venditti, A., Mazzone, C., Bruno, A., Gianní, L., Capelli, G., Lo Coco, F., Cantonetti, M., Gattei, V., Amadori, S. Cancer (2005) [Pubmed]
  11. Trichostatin A down-regulates ZAP-70, LAT and SLP-76 content in Jurkat T cells. Januchowski, R., Jagodzinski, P.P. Int. Immunopharmacol. (2007) [Pubmed]
  12. Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. Lühder, F., Huang, Y., Dennehy, K.M., Guntermann, C., Müller, I., Winkler, E., Kerkau, T., Ikemizu, S., Davis, S.J., Hanke, T., Hünig, T. J. Exp. Med. (2003) [Pubmed]
  13. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Seggewiss, R., Loré, K., Greiner, E., Magnusson, M.K., Price, D.A., Douek, D.C., Dunbar, C.E., Wiestner, A. Blood (2005) [Pubmed]
  14. Molecular cloning of SKAP55, a novel protein that associates with the protein tyrosine kinase p59fyn in human T-lymphocytes. Marie-Cardine, A., Bruyns, E., Eckerskorn, C., Kirchgessner, H., Meuer, S.C., Schraven, B. J. Biol. Chem. (1997) [Pubmed]
  15. MHC class I ligation of human T cells activates the ZAP70 and p56lck tyrosine kinases, leads to an alternative phenotype of the TCR/CD3 zeta-chain, and induces apoptosis. Skov, S., Bregenholt, S., Claesson, M.H. J. Immunol. (1997) [Pubmed]
  16. Identification of a novel dimeric phosphoprotein (PP29/30) associated with signaling receptors in human T lymphocytes and natural killer cells. Schraven, B., Ratnofsky, S., Gaumont, Y., Lindegger, H., Kirchgessner, H., Bruyns, E., Moebius, U., Meuer, S.C. J. Exp. Med. (1994) [Pubmed]
  17. T cell receptor (TCR) engagement in apoptosis-defective, but interleukin 2 (IL-2)-producing, T cells results in impaired ZAP70/CD3-zeta association. Sahuquillo, A.G., Roumier, A., Teixeiro, E., Bragado, R., Alarcón, B. J. Exp. Med. (1998) [Pubmed]
  18. Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. Faith, A., Akdis, C.A., Akdis, M., Simon, H.U., Blaser, K. J. Immunol. (1997) [Pubmed]
  19. Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Patankar, M.S., Jing, Y., Morrison, J.C., Belisle, J.A., Lattanzio, F.A., Deng, Y., Wong, N.K., Morris, H.R., Dell, A., Clark, G.F. Gynecol. Oncol. (2005) [Pubmed]
  20. In the immune synapse, ZAP-70 controls T cell polarization and recruitment of signaling proteins but not formation of the synaptic pattern. Blanchard, N., Di Bartolo, V., Hivroz, C. Immunity (2002) [Pubmed]
  21. The real LAT steps forward. Cantrell, D. Trends Cell Biol. (1998) [Pubmed]
  22. Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal structure and catalytic activity. Jin, Y.J., Yu, C.L., Burakoff, S.J. J. Biol. Chem. (1999) [Pubmed]
  23. Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. Di Bartolo, V., Mège, D., Germain, V., Pelosi, M., Dufour, E., Michel, F., Magistrelli, G., Isacchi, A., Acuto, O. J. Biol. Chem. (1999) [Pubmed]
  24. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Deindl, S., Kadlecek, T.A., Brdicka, T., Cao, X., Weiss, A., Kuriyan, J. Cell (2007) [Pubmed]
  25. The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling. Han, J., Kori, R., Shui, J.W., Chen, Y.R., Yao, Z., Tan, T.H. J. Biol. Chem. (2003) [Pubmed]
  26. Interaction of human MUC1 and beta-catenin is regulated by Lck and ZAP-70 in activated Jurkat T cells. Li, Q., Ren, J., Kufe, D. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  27. Tyrosine phosphorylation and recruitment of ZAP-70 to the CD3-TCR complex are defective after CD2 stimulation. Hubert, P., Lang, V., Debré, P., Bismuth, G. J. Immunol. (1996) [Pubmed]
  28. Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation. Pacini, S., Ulivieri, C., Di Somma, M.M., Isacchi, A., Lanfrancone, L., Pelicci, P.G., Telford, J.L., Baldari, C.T. J. Biol. Chem. (1998) [Pubmed]
  29. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. Wardenburg, J.B., Fu, C., Jackman, J.K., Flotow, H., Wilkinson, S.E., Williams, D.H., Johnson, R., Kong, G., Chan, A.C., Findell, P.R. J. Biol. Chem. (1996) [Pubmed]
  30. A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T cells. Lang, V., Mège, D., Semichon, M., Gary-Gouy, H., Bismuth, G. Eur. J. Immunol. (1997) [Pubmed]
  31. Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function. Chan, A.C., Dalton, M., Johnson, R., Kong, G.H., Wang, T., Thoma, R., Kurosaki, T. EMBO J. (1995) [Pubmed]
  32. Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine. Kremer, K.N., Humphreys, T.D., Kumar, A., Qian, N.X., Hedin, K.E. J. Immunol. (2003) [Pubmed]
  33. TNF activates Syk protein tyrosine kinase leading to TNF-induced MAPK activation, NF-kappaB activation, and apoptosis. Takada, Y., Aggarwal, B.B. J. Immunol. (2004) [Pubmed]
  34. CD44 signaling through p56lck involves lateral association with CD4 in human CD4+ T cells. Dianzani, U., Bragardo, M., Tosti, A., Ruggeri, L., Volpi, I., Casucci, M., Bottarel, F., Feito, M.J., Bonissoni, S., Velardi, A. Int. Immunol. (1999) [Pubmed]
  35. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Plas, D.R., Johnson, R., Pingel, J.T., Matthews, R.J., Dalton, M., Roy, G., Chan, A.C., Thomas, M.L. Science (1996) [Pubmed]
  36. SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling. Tang, J., Sawasdikosol, S., Chang, J.H., Burakoff, S.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  37. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Chen, L., Widhopf, G., Huynh, L., Rassenti, L., Rai, K.R., Weiss, A., Kipps, T.J. Blood (2002) [Pubmed]
  38. Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. Ticchioni, M., Charvet, C., Noraz, N., Lamy, L., Steinberg, M., Bernard, A., Deckert, M. Blood (2002) [Pubmed]
  39. The hetero-oligomeric antigen receptor complex and its coupling to cytoplasmic effectors. Cambier, J.C., Jensen, W.A. Curr. Opin. Genet. Dev. (1994) [Pubmed]
  40. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Schroers, R., Griesinger, F., Trümper, L., Haase, D., Kulle, B., Klein-Hitpass, L., Sellmann, L., Dührsen, U., Dürig, J. Leukemia (2005) [Pubmed]
  41. Association of a 70-kDa tyrosine phosphoprotein with the CD16: zeta: gamma complex expressed in human natural killer cells. Vivier, E., da Silva, A.J., Ackerly, M., Levine, H., Rudd, C.E., Anderson, P. Eur. J. Immunol. (1993) [Pubmed]
  42. SPAP2, an Ig family receptor containing both ITIMs and ITAMs. Xu, M.J., Zhao, R., Cao, H., Zhao, Z.J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
WikiGenes - Universities