ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of T cells and natural killer cells. It is part of the T cell receptor, and plays a critical role in T-cell signaling. Its molecular weight is 70 kDa, and it is a member of the protein-tyrosine kinase family.
ZAP-70 in B cells is used as a prognostic marker in identifying different forms of chronic lymphocytic leukemia (CLL). DNA analysis has distinguished two major types of CLL, with different survival times. CLL that is positive for the marker ZAP-70 has an average survival of 8 years. CLL that is negative for ZAP-70 has an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.
T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e. macrophages, dendritic cells and B cells) via the MHC complex. Upon this activation, the TCR co-receptor CD4 or CD8 binds to the MHC complex, activating the co-receptor associated tyrosine kinase Lck. Lck phosphorylates the intracellular portions of the CD3 complex (called ITAMs), creating a docking site for ZAP-70. 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 linker of activated T cells (LAT). Phosphorylated LAT, in turn, serves as a docking site to which a number of signaling proteins bind including SLP-76. 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.
Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J (2007). "Structural Basis for the Inhibition of Tyrosine Kinase Activity of ZAP-70". Cell129 (4): 735–46. doi:10.1016/j.cell.2007.03.039. PMID17512407.
Goldman F, Jensen WA, Johnson GL et al. (1994). "gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation.". J. Immunol.153 (7): 2905–17. PMID7522245.CS1 maint: Explicit use of et al. (link)
Nel AE, Gupta S, Lee L et al. (1995). "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.". J. Biol. Chem.270 (31): 18428–36. doi:10.1074/jbc.270.31.18428. PMID7629168.CS1 maint: Explicit use of et al. (link)
Negishi I, Motoyama N, Nakayama K et al. (1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes.". Nature376 (6539): 435–8. doi:10.1038/376435a0. PMID7630421.CS1 maint: Explicit use of et al. (link)
Mustelin T, Williams S, Tailor P et al. (1995). "Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase.". Eur. J. Immunol.25 (4): 942–6. doi:10.1002/eji.1830250413. PMID7737297.CS1 maint: Explicit use of et al. (link)
Katzav S, Sutherland M, Packham G et al. (1995). "The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav.". J. Biol. Chem.269 (51): 32579–85. PMID7798261.CS1 maint: Explicit use of et al. (link)
Schumann G, Dasgupta JD (1995). "Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif.". Int. Immunol.6 (9): 1383–92. doi:10.1093/intimm/6.9.1383. PMID7819147.
Watts JD, Affolter M, Krebs DL et al. (1994). "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.". J. Biol. Chem.269 (47): 29520–9. PMID7961936.CS1 maint: Explicit use of et al. (link)
Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.". Immunogenetics40 (4): 300–2. doi:10.1007/BF00189976. PMID8082894.
Chan AC, van Oers NS, Tran A et al. (1994). "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.152 (10): 4758–66. PMID8176201.CS1 maint: Explicit use of et al. (link)
Elder ME, Lin D, Clever J et al. (1994). "Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase.". Science264 (5165): 1596–9. doi:10.1126/science.8202712. PMID8202712.CS1 maint: Explicit use of et al. (link)
Chan AC, Kadlecek TA, Elder ME et al. (1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.". Science264 (5165): 1599–601. doi:10.1126/science.8202713. PMID8202713.CS1 maint: Explicit use of et al. (link)
Wange RL, Malek SN, Desiderio S, Samelson LE (1993). "Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells.". J. Biol. Chem.268 (26): 19797–801. PMID8366117.
Huby RD, Carlile GW, Ley SC (1996). "Interactions between the protein-tyrosine kinase ZAP-70, the proto-oncoprotein Vav, and tubulin in Jurkat T cells.". J. Biol. Chem.270 (51): 30241–4. doi:10.1074/jbc.270.51.30241. PMID8530437.
Plas DR, Johnson R, Pingel JT et al. (1996). "Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling.". Science272 (5265): 1173–6. doi:10.1126/science.272.5265.1173. PMID8638162.CS1 maint: Explicit use of et al. (link)
Wardenburg JB, Fu C, Jackman JK et al. (1996). "Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function.". J. Biol. Chem.271 (33): 19641–4. doi:10.1074/jbc.271.33.19641. PMID8702662.CS1 maint: Explicit use of et al. (link)
^Pelosi, M; Di Bartolo V; Mounier V; Mège D; Pascussi J M; Dufour E; Blondel A; Acuto O (May 1999). "Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck". J. Biol. Chem. (UNITED STATES) 274 (20): 14229–37. doi:10.1074/jbc.274.20.14229. ISSN0021-9258. PMID10318843.
^Perez-Villar, Juan J; Whitney Gena S, Sitnick Mitchell T, Dunn Robert J, Venkatesan Srividhya, O'Day Kathleen, Schieven Gary L, Lin Tai-An, Kanner Steven B (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry (United States) 41 (34): 10732–40. doi:10.1021/bi025554o. ISSN0006-2960. PMID12186560.Cite uses deprecated parameter |coauthors= (help)
^Lupher, M L; Reedquist K A; Miyake S; Langdon W Y; Band H (September 1996). "A novel phosphotyrosine-binding domain in the N-terminal transforming region of Cbl interacts directly and selectively with ZAP-70 in T cells". J. Biol. Chem. (UNITED STATES) 271 (39): 24063–8. doi:10.1074/jbc.271.39.24063. ISSN0021-9258. PMID8798643.
^Meng, W; Sawasdikosol S; Burakoff S J; Eck M J (March 1999). "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase". Nature (ENGLAND) 398 (6722): 84–90. doi:10.1038/18050. ISSN0028-0836. PMID10078535.
^Han, Jin; Kori Rajashree; Shui Jr-Wen; Chen Yi-Rong; Yao Zhengbin; Tan Tse-Hua (Dec 2003). "The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling". J. Biol. Chem. (United States) 278 (52): 52195–202. doi:10.1074/jbc.M305026200. ISSN0021-9258. PMID14557276.
^Pacini, S; Ulivieri C; Di Somma M M; Isacchi A; Lanfrancone L; Pelicci P G; Telford J L; Baldari C T (August 1998). "Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation". J. Biol. Chem. (UNITED STATES) 273 (32): 20487–93. doi:10.1074/jbc.273.32.20487. ISSN0021-9258. PMID9685404.