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]

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]