ZAP-70 Information & ZAP-70 Links at HealthHaven.com

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
Gene ontology
Molecular function	• nucleotide binding; • protein serine/threonine kinase activity; • protein-tyrosine kinase activity; • non-membrane spanning protein tyrosine kinase activity; • protein binding; • ATP binding; • transferase activity;
Cellular component	• cytoplasm; • membrane; • integral to membrane; • T cell receptor complex;
Biological process	• protein amino acid phosphorylation; • immune response; • protein kinase cascade; • positive thymic T cell selection; • positive regulation of T cell differentiation;
RNA expression pattern
	More reference expression data
Orthologs
NP_001070 (protein)	NP_033565 (protein)

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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.

[edit] 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.

[edit] 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.

[edit] Interactions

ZAP-70 has been shown to interact with Lck,^[1]^[2] FYN,^[3] SHB,^[4] Linker of activated T cells,^[5]^[6] Cbl gene,^[7]^[8] Drebrin-like^[9] and SHC1.^[10]

[edit] See also

Lck
Syk

[edit] 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. 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. 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. 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.

[edit] References

^ 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. ISSN 0021-9258. PMID 10318843.
^ 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". J. Exp. Med. (UNITED STATES) 181 (6): 1997-2006. ISSN 0022-1007. PMID 7539035.
^ Neumeister, E N; Zhu Y, Richard S, Terhorst C, Chan A C, Shaw A S (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". Mol. Cell. Biol. (UNITED STATES) 15 (6): 3171-8. ISSN 0270-7306. PMID 7760813.
^ Lindholm, Cecilia K; Henriksson Maria L, Hallberg Bengt, Welsh Michael (Jul. 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". Eur. J. Biochem. (Germany) 269 (13): 3279-88. ISSN 0014-2956. PMID 12084069.
^ Paz, P E; 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". Biochem. J. (England) 356 (Pt 2): 461-71. ISSN 0264-6021. PMID 11368773.
^ 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 (Aug. 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry (United States) 41 (34): 10732-40. ISSN 0006-2960. PMID 12186560.
^ Lupher, M L; Reedquist K A, Miyake S, Langdon W Y, 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". J. Biol. Chem. (UNITED STATES) 271 (39): 24063-8. ISSN 0021-9258. PMID 8798643.
^ Meng, W; Sawasdikosol S, Burakoff S J, Eck M J (Mar. 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 10078523.
^ 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.
^ Pacini, S; Ulivieri C, Di Somma M M, Isacchi A, Lanfrancone L, Pelicci P G, Telford J L, Baldari C T (Aug. 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. ISSN 0021-9258. PMID 9685404.

[edit] External links

MeSH ZAP-70+Protein

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[pmid10318843-0] 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. ISSN 0021-9258. PMID 10318843.

[pmid7539035-1] 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". J. Exp. Med. (UNITED STATES) 181 (6): 1997-2006. ISSN 0022-1007. PMID 7539035.

[pmid7760813-2] Neumeister, E N; Zhu Y, Richard S, Terhorst C, Chan A C, Shaw A S (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". Mol. Cell. Biol. (UNITED STATES) 15 (6): 3171-8. ISSN 0270-7306. PMID 7760813.

[pmid12084069-3] Lindholm, Cecilia K; Henriksson Maria L, Hallberg Bengt, Welsh Michael (Jul. 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". Eur. J. Biochem. (Germany) 269 (13): 3279-88. ISSN 0014-2956. PMID 12084069.

[pmid11368773-4] Paz, P E; 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". Biochem. J. (England) 356 (Pt 2): 461-71. ISSN 0264-6021. PMID 11368773.

[pmid12186560-5] 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 (Aug. 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry (United States) 41 (34): 10732-40. ISSN 0006-2960. PMID 12186560.

[pmid8798643-6] Lupher, M L; Reedquist K A, Miyake S, Langdon W Y, 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". J. Biol. Chem. (UNITED STATES) 271 (39): 24063-8. ISSN 0021-9258. PMID 8798643.

[pmid10078535-7] Meng, W; Sawasdikosol S, Burakoff S J, Eck M J (Mar. 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 10078523.

[pmid14557276-8] 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.

[pmid9685404-9] Pacini, S; Ulivieri C, Di Somma M M, Isacchi A, Lanfrancone L, Pelicci P G, Telford J L, Baldari C T (Aug. 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. ISSN 0021-9258. PMID 9685404.

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