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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).[1] It is part of the T cell receptor, and plays a critical role in T-cell signaling.

ZAP-70 was initially discovered in TCR-stimulated Jurkat cells, an immortal line of human T lymphocytes, in 1991.[2] Its molecular weight is 70 kDa, and it is a member of the protein-tyrosine kinase family. The importance of ZAP-70 in T cell activation was determined when comparing ZAP-70 expression in patients with SCID (severe combined immunodeficiency).[2] 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.[2] ZAP-70 expression in B cells is correlated with the development of chronic lymphocytic leukemia (CLL).

Function

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This figure shows ZAP-70's role in T cell signal transduction, from the TCR binding the MHC antigen complex to the activation of further signals.

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[3].

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.[4] 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).[4] Phosphorylated LAT, in turn, serves as a docking site to which a number of signalling proteins bind including the SH2-domain-containing leukocyte protein of 76 kDa (SLP-76).[4] SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.[5] 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

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Due to its role in lymphocyte signaling, ZAP-70 has been associated with diseases affecting lymphocytes. ZAP-70 expression is a significant indicator of the overall survival and event free survival of lymphocytes and has been associated with chronic lymphocytic leukemia (CLL).[6] CLL is a cancer that develops from overproduction of B cells in the bone marrow.

In individuals with CLL, higher levels of ZAP-70 is associated with a higher number of lymphocytes activated, as expression of ZAP-70 is associated with B cell malignancies in CLL.[1] Increased expression of ZAP-70 in B cell malignancies is correlated with increased activation of the B cell receptor, allowing for the use of ZAP-70 in B cells as a prognostic biomarker in identifying different forms of CLL.[1][6] 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.[7]

In systemic lupus erythematosus, the Zap-70 receptor pathway is missing and Syk takes its place.[8]

ZAP-70 deficiency results in a form of autosomal recessive immune deficiency named combined immunodeficiency.[9] Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells.[9] Patients were also found to have irregular lymphocyte proliferation responses.[9] These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.[9]

Interactions

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ZAP-70 has been shown to interact with:

See also

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References

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  1. ^ a b c 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ a b c 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.
  3. ^ Au-Yeung, Byron B.; Shah, Neel H.; Shen, Lin; Weiss, Arthur (04 26, 2018). "ZAP-70 in Signaling, Biology, and Disease". Annual Review of Immunology. 36: 127–156. doi:10.1146/annurev-immunol-042617-053335. ISSN 1545-3278. PMID 29237129. {{cite journal}}: Check date values in: |date= (help)
  4. ^ a b c 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.
  5. ^ Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C (2017-07-07). "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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ a b Liu, Yini; Wang, Yangfeng; Yang, Jule; Bi, Yongyi; Wang, Hong (2018-08). "ZAP-70 in chronic lymphocytic leukemia: A meta-analysis". Clinica Chimica Acta; International Journal of Clinical Chemistry. 483: 82–88. doi:10.1016/j.cca.2018.04.026. ISSN 1873-3492. PMID 29680229. {{cite journal}}: Check date values in: |date= (help)
  7. ^ 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.
  8. ^ NEJM 365:2110
  9. ^ a b c d Shirkani, Afshin; Shahrooei, Mohammad; Azizi, Gholamreza; Rokni-Zadeh, Hassan; Abolhassani, Hassan; Farrokhi, Shokrollah; Frans, Glynis; Bossuyt, Xavier; Aghamohammadi, Asghar (2017-01). "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. ISSN 1532-4311. PMID 27759478. {{cite journal}}: Check date values in: |date= (help)
  10. ^ 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.
  11. ^ 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. doi:10.1038/18050. PMID 10078535. S2CID 4411124.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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. doi:10.1074/jbc.274.20.14229. PMID 10318843.
  15. ^ 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.
  16. ^ 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.
  17. ^ Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB (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.
  18. ^ 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.
  19. ^ Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, Telford JL, Baldari CT (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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Category:Tyrosine kinases

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