ZAP70

ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells).^[5] It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.

ZAP70
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4XZ0, 1FBV, 1M61, 1U59, 2CBL, 2OQ1, 2OZO, 2Y1N, 3ZNI, 4A4B, 4A4C, 4K2R, 4XZ1
Identifiers
Aliases	ZAP70, SRK, STCD, STD, TZK, ZAP-70, zeta chain of T cell receptor associated protein kinase 70kDa, zeta chain of T cell receptor associated protein kinase 70, zeta chain of T-cell receptor associated protein kinase 70, IMD48, ADMIO2
External IDs	OMIM: 176947; MGI: 99613; HomoloGene: 839; GeneCards: ZAP70; OMA:ZAP70 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q11.2 Start 97,713,576 bp[1] End 97,739,862 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 B|1 15.41 cM Start 36,800,879 bp[2] End 36,821,899 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte lymph node blood spleen appendix thymus testicle gallbladder upper lobe of left lung mucosa of transverse colon Top expressed in thymus mesenteric lymph nodes white pulp blood left lobe of liver morula embryo dentate gyrus of hippocampal formation granule cell embryo blastocyst More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity non-membrane spanning protein tyrosine kinase activity kinase activity protein binding protein tyrosine kinase activity signaling receptor binding ATP binding phosphotyrosine residue binding Cellular component cytoplasm cytosol membrane cell-cell junction extrinsic component of cytoplasmic side of plasma membrane plasma membrane T cell receptor complex immunological synapse membrane raft Biological process positive regulation of T cell differentiation T cell migration positive regulation of calcium-mediated signaling intracellular signal transduction adaptive immune response phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway immune system process T cell aggregation beta selection negative thymic T cell selection protein phosphorylation B cell activation T cell differentiation immune response positive thymic T cell selection peptidyl-tyrosine autophosphorylation protein autophosphorylation peptidyl-tyrosine phosphorylation innate immune response T cell receptor signaling pathway thymic T cell selection positive regulation of alpha-beta T cell differentiation T cell activation regulation of cell population proliferation positive regulation of alpha-beta T cell proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7535 22637 Ensembl ENSG00000115085 ENSMUSG00000026117 UniProt P43403 P43404 RefSeq (mRNA) NM_001079 NM_207519 NM_001378594 NM_009539 NM_001289612 NM_001289765 NM_001289766 RefSeq (protein) NP_001070 NP_997402 NP_001365523 NP_001276541 NP_001276694 NP_001276695 NP_033565 Location (UCSC) Chr 2: 97.71 – 97.74 Mb Chr 1: 36.8 – 36.82 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ZAP-70 was initially discovered in TCR-stimulated Jurkat cells, an immortal line of human T lymphocytes, in 1991.^[6] Its molecular weight is 70 kDa, and it is a member of the protein-tyrosine kinase family and is a close homolog of SYK. SYK and ZAP70 share a common evolutionary origin and split from a common ancestor in the jawed vertebrates. ^[7] The importance of ZAP-70 in T cell activation was determined when comparing ZAP-70 expression in patients with SCID (severe combined immunodeficiency).^[6] ZAP-70 deficient individuals were found to have no functioning T cells in their peripheral blood, suggesting that ZAP-70 is a critical component of T cell activation and development.^[6]

ZAP-70 expression in B cells is correlated with the development of chronic lymphocytic leukemia (CLL).

Function

The T cell receptor has no innate enzymatic activity. Due to this, T cell receptors rely on signaling molecules to transduce a signal from the cell membrane. ZAP-70 is a critical cytoplasmic tyrosine kinase that initiates a signal pathway downstream of an activated T cell receptor.^[8]

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, Langerhans cells and B cells) via the MHC. Upon this activation, the TCR co-receptor CD4 (expressed on T helper cells) or CD8 (expressed on cytotoxic T cells) binds to the MHC, activating the co-receptor associated tyrosine kinase Lck. Lck is moved near the CD3 complex and phosphorylates the tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMS), creating a docking site for ZAP-70.^[9] 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 for activation of T cells (LAT).^[9] Phosphorylated LAT, in turn, serves as a docking site to which a number of signaling proteins bind, including the SH2-domain-containing leukocyte protein of 76 kDa (SLP-76).^[9] SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.^[10] 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.

Clinical Significance

Due to its role in lymphocyte signaling, ZAP-70 has been associated with several diseases affecting lymphocytes. ZAP-70 expression is a significant indicator of the survival of lymphocytes and has been notably associated with chronic lymphocytic leukemia (CLL).^[11] CLL is a cancer that develops from overproduction of B cells in the bone marrow.

In people with CLL, higher levels of ZAP-70 confers a worse prognosis; CLL patients that are positive for the marker ZAP-70 have an average survival of 8 years, whereas those that are negative for ZAP-70 have 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.^[12] In individuals with CLL, higher levels of ZAP-70 is associated with a higher number of malignant B cells activated.^[5] Increased expression of ZAP-70 in B cell malignancies is correlated with increased association between malignant B cells and the immune environment, suggesting a complex role for ZAP-70 in B cell signaling.^[5]

In systemic lupus erythematosus, the Zap-70 receptor pathway is missing and the homolog Syk takes its place.^[13]

ZAP-70 deficiency results in a form of autosomal recessive immune deficiency named combined immunodeficiency.^[14] Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells.^[14] Patients were also found to have irregular lymphocyte proliferation responses.^[14] These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.^[14]

Interactions

ZAP-70 has been shown to interact with:

• Cbl gene,^[15][16]
• Drebrin-like,^[17]
• FYN,^[18]
• Lck,^[19][20]
• LAT,^[21][22]
• SHB,^[23] and
• SHC1.^[24]

See also

• Lck
• Syk
• T cell receptor
• Chronic lymphocytic leukemia
• Combined immunodeficiency

References

1. GRCh38: Ensembl release 89: ENSG00000115085 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026117 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Chen J, Moore A, Ringshausen I (2020). "ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies". Frontiers in Oncology. 10: 595832. doi:10.3389/fonc.2020.595832. PMC 7653097. PMID 33194762.
6. Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A (May 2010). "ZAP-70: an essential kinase in T-cell signaling". Cold Spring Harbor Perspectives in Biology. 2 (5): a002279. doi:10.1101/cshperspect.a002279. PMC 2857167. PMID 20452964.
7. Staal, Jens; Driege, Yasmine; Haegman, Mira; Borghi, Alice; Hulpiau, Paco; Lievens, Laurens; Gul, Ismail Sahin; Sundararaman, Srividhya; Gonçalves, Amanda; Dhondt, Ineke; Pinzón, Jorge H.; Braeckman, Bart P.; Technau, Ulrich; Saeys, Yvan; van Roy, Frans (2018-05-24). "Ancient Origin of the CARD–Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions". Frontiers in Immunology. 9: 1136. doi:10.3389/fimmu.2018.01136. ISSN 1664-3224. PMC 5978004. PMID 29881386.
8. Au-Yeung BB, Shah NH, Shen L, Weiss A (April 2018). "ZAP-70 in Signaling, Biology, and Disease". Annual Review of Immunology. 36: 127–156. doi:10.1146/annurev-immunol-042617-053335. PMID 29237129.
9. Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A (May 2010). "ZAP-70: an essential kinase in T-cell signaling". Cold Spring Harbor Perspectives in Biology. 2 (5): a002279. doi:10.1101/cshperspect.a002279. PMC 2857167. PMID 20452964.
10. Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C (2017). "Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes". Frontiers in Immunology. 8: 789. doi:10.3389/fimmu.2017.00789. PMC 5500614. PMID 28736554.
11. Liu, Yini; Wang, Yangfeng; Yang, Jule; Bi, Yongyi; Wang, Hong (August 2018). "ZAP-70 in chronic lymphocytic leukemia: A meta-analysis". Clinica Chimica Acta. 483: 82–88. doi:10.1016/j.cca.2018.04.026. PMID 29680229. S2CID 5040894.
12. Chiorazzi N, Rai KR, Ferrarini M (February 2005). "Chronic lymphocytic leukemia". The New England Journal of Medicine. 352 (8): 804–15. doi:10.1056/NEJMra041720. PMID 15728813.
13. Tsokos GC (December 2011). "Systemic lupus erythematosus". The New England Journal of Medicine. 365 (22): 2110–21. doi:10.1056/NEJMra1100359. PMID 22129255.
14. Shirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H, Farrokhi S, et al. (January 2017). "Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature". Immunological Investigations. 46 (1): 70–79. doi:10.1080/08820139.2016.1214962. PMID 27759478. S2CID 30518855.
15. Lupher ML, Reedquist KA, Miyake S, Langdon WY, 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". The Journal of Biological Chemistry. 271 (39): 24063–8. doi:10.1074/jbc.271.39.24063. PMID 8798643.
16. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ (March 1999). "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase". Nature. 398 (6722): 84–90. Bibcode:1999Natur.398...84M. doi:10.1038/18050. PMID 10078535. S2CID 4411124.
17. Han J, Kori R, Shui JW, Chen YR, Yao Z, Tan TH (December 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.
18. Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (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". Molecular and Cellular Biology. 15 (6): 3171–8. doi:10.1128/mcb.15.6.3171. PMC 230549. PMID 7760813.
19. Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, et al. (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. doi:10.1074/jbc.274.20.14229. PMID 10318843.
20. 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". The Journal of Experimental Medicine. 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070. PMID 7539035.
21. Paz PE, 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". The Biochemical Journal. 356 (Pt 2): 461–71. doi:10.1042/bj3560461. PMC 1221857. PMID 11368773.
22. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, et al. (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry. 41 (34): 10732–40. doi:10.1021/bi025554o. PMID 12186560.
23. Lindholm CK, Henriksson ML, Hallberg B, Welsh M (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry. 269 (13): 3279–88. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069.
24. Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, et al. (August 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. doi:10.1074/jbc.273.32.20487. PMID 9685404.

Further reading

• Chan AC, Iwashima M, Turck CW, Weiss A (November 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. S2CID 54326428.
• 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. S2CID 16593136.
• Orchard J, Ibbotson R, Best G, Parker A, Oscier D (December 2005). "ZAP-70 in B cell malignancies". Leukemia & Lymphoma. 46 (12): 1689–98. doi:10.1080/09638280500260079. PMID 16263570. S2CID 30981389.
• Hamblin AD, Hamblin TJ (December 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. S2CID 20808988.
• Chan AC, Iwashima M, Turck CW, Weiss A (November 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. S2CID 54326428.
• Goldman F, Jensen WA, Johnson GL, Heasley L, Cambier JC (October 1994). "gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation". Journal of Immunology. 153 (7): 2905–17. doi:10.4049/jimmunol.153.7.2905. PMID 7522245. S2CID 32770138.
• Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE (January 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 (August 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, et al. (August 1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes". Nature. 376 (6539): 435–8. Bibcode:1995Natur.376..435N. doi:10.1038/376435a0. PMID 7630421. S2CID 4366344.
• Mustelin T, Williams S, Tailor P, Couture C, Zenner G, Burn P, et al. (April 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. S2CID 19309659.
• Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (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". Molecular and Cellular Biology. 15 (6): 3171–8. doi:10.1128/mcb.15.6.3171. PMC 230549. PMID 7760813.
• Katzav S, Sutherland M, Packham G, Yi T, Weiss A (December 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. doi:10.1016/S0021-9258(18)31673-9. PMID 7798261.
• Schumann G, Dasgupta JD (September 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 (November 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. doi:10.1016/S0021-9258(18)43911-7. 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. S2CID 33774157.
• Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, et al. (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. doi:10.4049/jimmunol.152.10.4758. PMID 8176201. S2CID 37831763.
• Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (June 1994). "Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase". Science. 264 (5165): 1596–9. Bibcode:1994Sci...264.1596E. doi:10.1126/science.8202712. PMID 8202712.
• Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, et al. (June 1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency". Science. 264 (5165): 1599–601. Bibcode:1994Sci...264.1599C. doi:10.1126/science.8202713. PMID 8202713.
• Wange RL, Malek SN, Desiderio S, Samelson LE (September 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. doi:10.1016/S0021-9258(19)36584-6. PMID 8366117.
• Huby RD, Carlile GW, Ley SC (December 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, et al. (May 1996). "Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling". Science. 272 (5265): 1173–6. Bibcode:1996Sci...272.1173P. doi:10.1126/science.272.5265.1173. PMID 8638162. S2CID 41401787.
• Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, et al. (August 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

• GeneReviews/NIH/NCBI/UW entry on ZAP70-Related Severe Combined Immunodeficiency
• ZAP-70+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)