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Gene Review

Zap70  -  zeta-chain (TCR) associated protein kinase

Mus musculus

Synonyms: 70 kDa zeta-chain associated protein, AI327364, Srk, Syk-related tyrosine kinase, TZK, ...
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Disease relevance of Zap70


High impact information on Zap70

  • Data from recent knockout experiments in cell lines and mice contradict the assumption that Src-family kinase and tyrosine kinases of the Syk/Zap-70 family are the transducer elements that set signaling from these receptors in motion [6].
  • This results in the phosphorylation of CD3epsilon and Zap-70 signal transducing molecules [7].
  • Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations [8].
  • Natural killer cell function was intact in the absence of ZAP-70 [8].
  • Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists [9].

Chemical compound and disease context of Zap70


Biological context of Zap70


Anatomical context of Zap70


Associations of Zap70 with chemical compounds

  • This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs [20].
  • This finding contradicts the accepted mechanism of c-Cbl-mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70 [21].
  • Furthermore, DP thymocytes with mutant receptors can respond to agonist ligand with normal antigen sensitivity and to normal levels, as shown by their ability to induce CD69 up-regulation, TCR down-regulation, negative selection, and ZAP70 and c-Jun NH2-terminal kinase activation [22].
  • We show that ZAP-70 is also required for migration of T cells that is dependent on the integrin LFA-1 [23].
  • LFA-1 cross-linking induced tyrosine phosphorylation, which was blocked by dominant-negative ZAP-70 and piceatannol [23].

Physical interactions of Zap70


Enzymatic interactions of Zap70

  • Thus, we propose that Fyn phosphorylates and activates ZAP-70 and that both kinases cooperate in TCR signaling [26].
  • At this time, ZAP-70 from both normal and c-Cbl-/- thymocytes becomes hyperphosphorylated; however, only in normal thymocytes does this correlate with ZAP-70 down-regulation and a diminished ability to phosphorylate LAT and SLP-76 [27].
  • Recruitment of ZAP-70 protein tyrosine kinase to the T cell antigen receptor (TCR) is mediated by the binding of the SH2 domains of this enzyme to phosphorylated ITAM motifs in the CD3 and TCRzeta subunits [28].

Regulatory relationships of Zap70


Other interactions of Zap70

  • The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions [29].
  • Moreover, ligation of the TCR expressed on thymocytes from Lck-deficient mice largely failed to induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70 [29].
  • Compared to Jurkat and HT-2 cells, fresh T cells show both higher baseline levels and lower induced levels of Zap-70 function in CD3zeta complexes [34].
  • Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP-70, MAP kinase activation, or IL-4/IL-10 secretion [17].
  • To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution at position 292 (Y292F) or 315 (Y315F) [35].
  • Our results establish a temporal separation of Syk family kinase function during early thymocyte development and a novel role for ZAP-70 [36].

Analytical, diagnostic and therapeutic context of Zap70

  • Northern blot analysis indicated that the expression of ZAP-70 mRNA was most pronounced in the thymus and spleen and also slightly in the brain [37].
  • Using a newly devised retrovirus gene transfer and an efficient green fluorescence protein detection technique in fetal thymus organ cultures, the present study shows that forced expression in developing thymocytes of a catalytically inactive mutant of ZAP-70, but not wild-type ZAP-70, inhibits T cell development at the earlier CD4-CD8- stage [38].
  • An improved retroviral gene transfer technique demonstrates inhibition of CD4-CD8- thymocyte development by kinase-inactive ZAP-70 [38].
  • Analysis of ZAP-70 and other signaling proteins of the pre-TCR/TCR was done by Western blot [39].
  • Improved treatment efficacy was achieved in infant ZAP-70-/- mice, in which the thymus is proportionately larger and a higher percentage of prothymocytes are in cycle [40].


  1. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Murphy, M.A., Schnall, R.G., Venter, D.J., Barnett, L., Bertoncello, I., Thien, C.B., Langdon, W.Y., Bowtell, D.D. Mol. Cell. Biol. (1998) [Pubmed]
  2. Restoration of thymic development in an Lck(-/-) thymoma overexpressing ZAP-70. Ulivieri, C., Majolini, M.B., Baldari, C.T. Mol. Immunol. (2000) [Pubmed]
  3. Defective recruitment and activation of ZAP-70 in common variable immunodeficiency patients with T cell defects. Boncristiano, M., Majolini, M.B., D'Elios, M.M., Pacini, S., Valensin, S., Ulivieri, C., Amedei, A., Falini, B., Del Prete, G., Telford, J.L., Baldari, C.T. Eur. J. Immunol. (2000) [Pubmed]
  4. Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. Kirken, R.A., Erwin, R.A., Taub, D., Murphy, W.J., Behbod, F., Wang, L., Pericle, F., Farrar, W.L. J. Leukoc. Biol. (1999) [Pubmed]
  5. T cells from late tumor-bearing mice express normal levels of p56lck, p59fyn, ZAP-70, and CD3 zeta despite suppressed cytolytic activity. Levey, D.L., Srivastava, P.K. J. Exp. Med. (1995) [Pubmed]
  6. Initiation and processing of signals from the B cell antigen receptor. Reth, M., Wienands, J. Annu. Rev. Immunol. (1997) [Pubmed]
  7. Different initiation of pre-TCR and gammadeltaTCR signalling. Saint-Ruf, C., Panigada, M., Azogui, O., Debey, P., von Boehmer, H., Grassi, F. Nature (2000) [Pubmed]
  8. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Negishi, I., Motoyama, N., Nakayama, K., Nakayama, K., Senju, S., Hatakeyama, S., Zhang, Q., Chan, A.C., Loh, D.Y. Nature (1995) [Pubmed]
  9. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Madrenas, J., Wange, R.L., Wang, J.L., Isakov, N., Samelson, L.E., Germain, R.N. Science (1995) [Pubmed]
  10. Reconstitution of lymphoid development and function in ZAP-70-deficient mice following gene transfer into bone marrow cells. Otsu, M., Steinberg, M., Ferrand, C., Merida, P., Rebouissou, C., Tiberghien, P., Taylor, N., Candotti, F., Noraz, N. Blood (2002) [Pubmed]
  11. Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection. Liu, X., Adams, A., Wildt, K.F., Aronow, B., Feigenbaum, L., Bosselut, R. J. Exp. Med. (2003) [Pubmed]
  12. Adaptive tolerance and clonal anergy are distinct biochemical states. Chiodetti, L., Choi, S., Barber, D.L., Schwartz, R.H. J. Immunol. (2006) [Pubmed]
  13. Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Carpino, N., Turner, S., Mekala, D., Takahashi, Y., Zang, H., Geiger, T.L., Doherty, P., Ihle, J.N. Immunity (2004) [Pubmed]
  14. Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes. Fournel, M., Davidson, D., Weil, R., Veillette, A. J. Exp. Med. (1996) [Pubmed]
  15. The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway. Salvador, J.M., Mittelstadt, P.R., Belova, G.I., Fornace, A.J., Ashwell, J.D. Nat. Immunol. (2005) [Pubmed]
  16. Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling. Chan, A.C., van Oers, N.S., Tran, A., Turka, L., Law, C.L., Ryan, J.C., Clark, E.A., Weiss, A. J. Immunol. (1994) [Pubmed]
  17. Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways. Feito, M.J., Vaschetto, R., Criado, G., Sánchez, A., Chiocchetti, A., Jiménez-Periáñez, A., Dianzani, U., Portoles, P., Rojo, J.M. Eur. J. Immunol. (2003) [Pubmed]
  18. A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Wiest, D.L., Ashe, J.M., Howcroft, T.K., Lee, H.M., Kemper, D.M., Negishi, I., Singer, D.S., Singer, A., Abe, R. Immunity (1997) [Pubmed]
  19. Regulation of T-cell antigen receptor signalling by Syk tyrosine protein kinase. Latour, S., Fournel, M., Veillette, A. Mol. Cell. Biol. (1997) [Pubmed]
  20. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Salvador, J.M., Mittelstadt, P.R., Guszczynski, T., Copeland, T.D., Yamaguchi, H., Appella, E., Fornace, A.J., Ashwell, J.D. Nat. Immunol. (2005) [Pubmed]
  21. A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase. Thien, C.B., Scaife, R.M., Papadimitriou, J.M., Murphy, M.A., Bowtell, D.D., Langdon, W.Y. J. Exp. Med. (2003) [Pubmed]
  22. Contributions of the T cell receptor-associated CD3gamma-ITAM to thymocyte selection. Haks, M.C., Pépin, E., van den Brakel, J.H., Smeele, S.A., Belkowski, S.M., Kessels, H.W., Krimpenfort, P., Kruisbeek, A.M. J. Exp. Med. (2002) [Pubmed]
  23. ZAP-70 tyrosine kinase is required for LFA-1-dependent T cell migration. Soede, R.D., Wijnands, Y.M., Van Kouteren-Cobzaru, I., Roos, E. J. Cell Biol. (1998) [Pubmed]
  24. The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70. Lupher, M.L., Songyang, Z., Shoelson, S.E., Cantley, L.C., Band, H. J. Biol. Chem. (1997) [Pubmed]
  25. The proto-oncogene Vav product is constitutively tyrosine-phosphorylated in normal human immature T cells. Gouy, H., Debré, P., Bismuth, G. Eur. J. Immunol. (1995) [Pubmed]
  26. Physical and functional interactions of protein tyrosine kinases, p59fyn and ZAP-70, in T cell signaling. Fusaki, N., Matsuda, S., Nishizumi, H., Umemori, H., Yamamoto, T. J. Immunol. (1996) [Pubmed]
  27. Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. Thien, C.B., Bowtell, D.D., Langdon, W.Y. J. Immunol. (1999) [Pubmed]
  28. Tyrosine 315 determines optimal recruitment of ZAP-70 to the T cell antigen receptor. Di Bartolo, V., Malissen, M., Dufour, E., Sechet, E., Malissen, B., Acuto, O. Eur. J. Immunol. (2002) [Pubmed]
  29. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. van Oers, N.S., Killeen, N., Weiss, A. J. Exp. Med. (1996) [Pubmed]
  30. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Naramura, M., Kole, H.K., Hu, R.J., Gu, H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. Michel, F., Grimaud, L., Tuosto, L., Acuto, O. J. Biol. Chem. (1998) [Pubmed]
  32. SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. Pivniouk, V.I., Martin, T.R., Lu-Kuo, J.M., Katz, H.R., Oettgen, H.C., Geha, R.S. J. Clin. Invest. (1999) [Pubmed]
  33. Regulation of Zap-70 by Src family tyrosine protein kinases in an antigen-specific T-cell line. Weil, R., Cloutier, J.F., Fournel, M., Veillette, A. J. Biol. Chem. (1995) [Pubmed]
  34. Increased Zap-70 association with CD3zeta in CD4 T cells from old mice. Garcia, G.G., Miller, R.A. Cell. Immunol. (1998) [Pubmed]
  35. T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase. Magnan, A., Di Bartolo, V., Mura, A.M., Boyer, C., Richelme, M., Lin, Y.L., Roure, A., Gillet, A., Arrieumerlou, C., Acuto, O., Malissen, B., Malissen, M. J. Exp. Med. (2001) [Pubmed]
  36. Distinct roles for Syk and ZAP-70 during early thymocyte development. Palacios, E.H., Weiss, A. J. Exp. Med. (2007) [Pubmed]
  37. Expression of ZAP-70 gene in the developing thymus and various nonlymphoid tissues of embryonic and adult mice. Ishijima, S.A., Zeng, Y.X., Kurashima, C., Utsuyama, M., Shirasawa, T., Sakamoto, K., Hirokawa, K. Cell. Immunol. (1995) [Pubmed]
  38. An improved retroviral gene transfer technique demonstrates inhibition of CD4-CD8- thymocyte development by kinase-inactive ZAP-70. Sugawara, T., Di Bartolo, V., Miyazaki, T., Nakauchi, H., Acuto, O., Takahama, Y. J. Immunol. (1998) [Pubmed]
  39. ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B-cell acute lymphoblastic leukemia. Crespo, M., Villamor, N., Giné, E., Muntañola, A., Colomer, D., Marafioti, T., Jones, M., Camós, M., Campo, E., Montserrat, E., Bosch, F. Clin. Cancer Res. (2006) [Pubmed]
  40. In vivo correction of ZAP-70 immunodeficiency by intrathymic gene transfer. Adjali, O., Marodon, G., Steinberg, M., Mongellaz, C., Thomas-Vaslin, V., Jacquet, C., Taylor, N., Klatzmann, D. J. Clin. Invest. (2005) [Pubmed]
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