ZAP70

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Zeta-chain (TCR) associated protein kinase 70kDa
Protein ZAP70 PDB 1m61.png
PDB rendering based on 1m61.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ZAP70 ; SRK; STCD; STD; TZK; ZAP-70
External IDs OMIM176947 MGI99613 HomoloGene839 ChEMBL: 2803 GeneCards: ZAP70 Gene
EC number 2.7.10.2
RNA expression pattern
PBB GE ZAP70 214032 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7535 22637
Ensembl ENSG00000115085 ENSMUSG00000026117
UniProt P43403 P43404
RefSeq (mRNA) NM_001079 NM_001289612
RefSeq (protein) NP_001070 NP_001276541
Location (UCSC) Chr 2:
98.33 – 98.36 Mb
Chr 1:
36.76 – 36.78 Mb
PubMed search [1] [2]

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.

Clinical significance[edit]

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.[1]

In systemic lupus erythematosus, the Zap-70 receptor pathway is missing and Syk takes its place.[2]

ZAP70 deficiency results in a form of immune deficiency.

Function[edit]

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) 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.

Interactions[edit]

ZAP-70 has been shown to interact with Lck,[3][4] FYN,[5] SHB,[6] LAT,[7][8] Cbl gene,[9][10] Drebrin-like[11] and SHC1.[12]

See also[edit]

Further reading[edit]

  • 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. doi:10.1016/0092-8674(92)90598-7. 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. doi:10.1016/0092-8674(92)90598-7. 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. doi:10.1084/jem.181.1.375. PMC 2191847. 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. doi:10.1074/jbc.270.31.18428. 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. doi:10.1002/eji.1830250413. 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. PMC 230549. 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. doi:10.1093/intimm/6.9.1383. 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. doi:10.1007/BF00189976. 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. doi:10.1126/science.8202712. 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. doi:10.1126/science.8202713. 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. doi:10.1074/jbc.270.51.30241. 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. doi:10.1126/science.272.5265.1173. 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. doi:10.1074/jbc.271.33.19641. PMID 8702662. 

References[edit]

  1. ^ Chiorazzi N, Rai KR, Ferrarini M (2005). "Chronic lymphocytic leukemia". N. Engl. J. Med. 352 (8): 804–15. doi:10.1056/NEJMra041720. PMID 15728813. 
  2. ^ NEJM 365:2110
  3. ^ 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. ISSN 0021-9258. PMID 10318843. 
  4. ^ Thome, M; Duplay P; Guttinger M; Acuto O (June 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". J. Exp. Med. (UNITED STATES) 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. ISSN 0022-1007. PMC 2192070. PMID 7539035. 
  5. ^ Neumeister, E N; Zhu Y; Richard S; Terhorst C; Chan A C; Shaw A S (June 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. (UNITED STATES) 15 (6): 3171–8. ISSN 0270-7306. PMC 230549. PMID 7760813. 
  6. ^ Lindholm, Cecilia K; Henriksson Maria L; Hallberg Bengt; Welsh Michael (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". Eur. J. Biochem. (Germany) 269 (13): 3279–88. doi:10.1046/j.1432-1033.2002.03008.x. ISSN 0014-2956. PMID 12084069. 
  7. ^ Paz, P E; Wang S; Clarke H; Lu X; Stokoe D; Abo A (June 2001). "Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells". Biochem. J. (England) 356 (Pt 2): 461–71. doi:10.1042/0264-6021:3560461. ISSN 0264-6021. PMC 1221857. PMID 11368773. 
  8. ^ 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. ISSN 0006-2960. PMID 12186560. 
  9. ^ 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. ISSN 0021-9258. PMID 8798643. 
  10. ^ 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. ISSN 0028-0836. PMID 10078535. 
  11. ^ 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. ISSN 0021-9258. PMID 14557276. 
  12. ^ 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. ISSN 0021-9258. PMID 9685404. 

External links[edit]