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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesZAP70, 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 IDsOMIM: 176947 MGI: 99613 HomoloGene: 839 GeneCards: ZAP70
Orthologs
SpeciesHumanMouse
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 MbChr 1: 36.8 – 36.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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:

See also

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
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