Zap-70

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Zeta-chain (TCR) associated protein kinase 70kDa
PDB rendering based on 1m61.
Available structures: 1m61, 1u59, 2oq1, 2ozo
Identifiers
Symbols ZAP70; SRK; STD; TZK; ZAP-70
External IDs OMIM: 176947 MGI: 99613 HomoloGene: 839
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 7535 22637
Ensembl ENSG00000115085 ENSMUSG00000026117
Uniprot P43403 P97455
Refseq NM_001079 (mRNA)
NP_001070 (protein)		 NM_009539 (mRNA)
NP_033565 (protein)
Location Chr 2: 97.7 - 97.72 Mb Chr 1: 36.71 - 36.73 Mb
Pubmed search [1] [2]

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.

Contents

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.

See also

Further reading

  • Chan AC, Iwashima M, Turck CW, Weiss A (1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell 71 (4): 649–62. PMID 1423621. 
  • 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". Cell 129 (4): 735–46. doi:10.1016/j.cell.2007.03.039. PMID 17512407. 
  • Orchard J, Ibbotson R, Best G, et al. (2006). "ZAP-70 in B cell malignancies.". Leuk. Lymphoma 46 (12): 1689–98. doi:10.1080/09638280500260079. PMID 16263570. 
  • Hamblin AD, Hamblin TJ (2006). "Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia.". Expert Opin. Ther. Targets 9 (6): 1165–78. doi:10.1517/14728222.9.6.1165. PMID 16300468. 
  • Chan AC, Iwashima M, Turck CW, Weiss A (1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.". Cell 71 (4): 649–62. PMID 1423621. 
  • 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. PMID 7522245. 
  • Isakov N, Wange RL, Burgess WH, et al. (1995). "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.". J. Exp. Med. 181 (1): 375–80. PMID 7528772. 
  • 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. PMID 7629168. 
  • Negishi I, Motoyama N, Nakayama K, et al. (1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes.". Nature 376 (6539): 435–8. doi:10.1038/376435a0. PMID 7630421. 
  • 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. PMID 7737297. 
  • Neumeister EN, Zhu Y, Richard S, et al. (1995). "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.". Mol. Cell. Biol. 15 (6): 3171–8. PMID 7760813. 
  • 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. PMID 7798261. 
  • 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. PMID 7819147. 
  • 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. PMID 7961936. 
  • Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.". Immunogenetics 40 (4): 300–2. PMID 8082894. 
  • 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. PMID 8176201. 
  • 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.". Science 264 (5165): 1596–9. PMID 8202712. 
  • Chan AC, Kadlecek TA, Elder ME, et al. (1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency.". Science 264 (5165): 1599–601. PMID 8202713. 
  • 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. PMID 8366117. 
  • 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. PMID 8530437. 
  • Plas DR, Johnson R, Pingel JT, et al. (1996). "Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling.". Science 272 (5265): 1173–6. PMID 8638162. 
  • 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. PMID 8702662. 

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