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:
97.71 – 97.74 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 (i.e. macrophages, dendritic cells and B cells) via the MHC. Upon this activation, the TCR co-receptor CD4 or CD8 binds to the MHC, 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:

See also[edit]

References[edit]

  1. ^ Chiorazzi N, Rai KR, Ferrarini M (Feb 2005). "Chronic lymphocytic leukemia". The New England Journal of Medicine 352 (8): 804–15. doi:10.1056/NEJMra041720. PMID 15728813. 
  2. ^ NEJM 365:2110
  3. ^ Lupher ML, Reedquist KA, Miyake S, Langdon WY, Band H (Sep 1996). "A novel phosphotyrosine-binding domain in the N-terminal transforming region of Cbl interacts directly and selectively with ZAP-70 in T cells". The Journal of Biological Chemistry 271 (39): 24063–8. PMID 8798643. 
  4. ^ Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ (Mar 1999). "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase". Nature 398 (6722): 84–90. doi:10.1038/18050. PMID 10078535. 
  5. ^ Han J, Kori R, Shui JW, Chen YR, Yao Z, Tan TH (Dec 2003). "The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling". The Journal of Biological Chemistry 278 (52): 52195–202. doi:10.1074/jbc.M305026200. PMID 14557276. 
  6. ^ Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (Jun 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". Molecular and Cellular Biology 15 (6): 3171–8. PMC 230549. PMID 7760813. 
  7. ^ Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, 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". The Journal of Biological Chemistry 274 (20): 14229–37. PMID 10318843. 
  8. ^ Thome M, Duplay P, Guttinger M, Acuto O (Jun 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine 181 (6): 1997–2006. PMC 2192070. PMID 7539035. 
  9. ^ Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A (Jun 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". The Biochemical Journal 356 (Pt 2): 461–71. PMC 1221857. PMID 11368773. 
  10. ^ Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB (Aug 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry 41 (34): 10732–40. PMID 12186560. 
  11. ^ Lindholm CK, Henriksson ML, Hallberg B, Welsh M (Jul 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry / FEBS 269 (13): 3279–88. PMID 12084069. 
  12. ^ Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, Telford JL, Baldari CT (Aug 1998). "Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation". The Journal of Biological Chemistry 273 (32): 20487–93. PMID 9685404. 

Further reading[edit]

  • Chan AC, Iwashima M, Turck CW, Weiss A (Nov 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 (May 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, Parker A, Oscier D (Dec 2005). "ZAP-70 in B cell malignancies". Leukemia & Lymphoma 46 (12): 1689–98. doi:10.1080/09638280500260079. PMID 16263570. 
  • Hamblin AD, Hamblin TJ (Dec 2005). "Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia". Expert Opinion on Therapeutic Targets 9 (6): 1165–78. doi:10.1517/14728222.9.6.1165. PMID 16300468. 
  • Chan AC, Iwashima M, Turck CW, Weiss A (Nov 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, Heasley L, Cambier JC (Oct 1994). "gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation". Journal of Immunology 153 (7): 2905–17. PMID 7522245. 
  • Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE (Jan 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". The Journal of Experimental Medicine 181 (1): 375–80. doi:10.1084/jem.181.1.375. PMC 2191847. PMID 7528772. 
  • Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB (Aug 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". The Journal of Biological Chemistry 270 (31): 18428–36. doi:10.1074/jbc.270.31.18428. PMID 7629168. 
  • Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, Zhang Q, Chan AC, Loh DY (Aug 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, Couture C, Zenner G, Burn P, Ashwell JD, Altman A (Apr 1995). "Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase". European Journal of Immunology 25 (4): 942–6. doi:10.1002/eji.1830250413. PMID 7737297. 
  • Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (Jun 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". Molecular and Cellular Biology 15 (6): 3171–8. PMC 230549. PMID 7760813. 
  • Katzav S, Sutherland M, Packham G, Yi T, Weiss A (Dec 1994). "The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav". The Journal of Biological Chemistry 269 (51): 32579–85. PMID 7798261. 
  • Schumann G, Dasgupta JD (Sep 1994). "Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif". International Immunology 6 (9): 1383–92. doi:10.1093/intimm/6.9.1383. PMID 7819147. 
  • Watts JD, Affolter M, Krebs DL, Wange RL, Samelson LE, Aebersold R (Nov 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". The Journal of Biological Chemistry 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, Turka L, Law CL, Ryan JC, Clark EA, Weiss A (May 1994). "Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling". Journal of Immunology 152 (10): 4758–66. PMID 8176201. 
  • Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (Jun 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, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A (Jun 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 (Sep 1993). "Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells". The Journal of Biological Chemistry 268 (26): 19797–801. PMID 8366117. 
  • Huby RD, Carlile GW, Ley SC (Dec 1995). "Interactions between the protein-tyrosine kinase ZAP-70, the proto-oncoprotein Vav, and tubulin in Jurkat T cells". The Journal of Biological Chemistry 270 (51): 30241–4. doi:10.1074/jbc.270.51.30241. PMID 8530437. 
  • Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC, Thomas ML (May 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. 
  • Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR (Aug 1996). "Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function". The Journal of Biological Chemistry 271 (33): 19641–4. doi:10.1074/jbc.271.33.19641. PMID 8702662. 


External links[edit]