Biology:ZAP70

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 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.

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 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. [3] 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

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.[4]

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.[5] 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).[5] 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).[5] SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.[6] 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).[7] 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.[8] In individuals with CLL, higher levels of ZAP-70 is associated with a higher number of malignant B cells activated.[1] 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.[1]

In systemic lupus erythematosus, the Zap-70 receptor pathway is missing and the homolog Syk takes its place.[9]

ZAP-70 deficiency results in a form of autosomal recessive immune deficiency named combined immunodeficiency.[10] Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells.[10] Patients were also found to have irregular lymphocyte proliferation responses.[10] These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.[10]

Interactions

ZAP-70 has been shown to interact with:


See also

References

  1. ↑ 1.0 1.1 1.2 "ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies". Frontiers in Oncology 10: 595832. 2020. doi:10.3389/fonc.2020.595832. PMID 33194762. 
  2. ↑ 2.0 2.1 2.2 "ZAP-70: an essential kinase in T-cell signaling". Cold Spring Harbor Perspectives in Biology 2 (5): a002279. May 2010. doi:10.1101/cshperspect.a002279. PMID 20452964. 
  3. ↑ Staal, Jens; Driege, Yasmine; Haegman, Mira; Borghi, Alice; Hulpiau, Paco; Lievens, Laurens; Gul, Ismail Sahin; Sundararaman, Srividhya et al. (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. PMID 29881386. 
  4. ↑ "ZAP-70 in Signaling, Biology, and Disease". Annual Review of Immunology 36: 127–156. April 2018. doi:10.1146/annurev-immunol-042617-053335. PMID 29237129. 
  5. ↑ 5.0 5.1 5.2 "ZAP-70: an essential kinase in T-cell signaling". Cold Spring Harbor Perspectives in Biology 2 (5): a002279. May 2010. doi:10.1101/cshperspect.a002279. PMID 20452964. 
  6. ↑ "Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes". Frontiers in Immunology 8: 789. 2017. doi:10.3389/fimmu.2017.00789. PMID 28736554. 
  7. ↑ Liu, Yini; Wang, Yangfeng; Yang, Jule; Bi, Yongyi; Wang, Hong (August 2018). "ZAP-70 in chronic lymphocytic leukemia: A meta-analysis" (in en). Clinica Chimica Acta 483: 82–88. doi:10.1016/j.cca.2018.04.026. PMID 29680229. https://linkinghub.elsevier.com/retrieve/pii/S0009898118301931. 
  8. ↑ "Chronic lymphocytic leukemia". The New England Journal of Medicine 352 (8): 804–15. February 2005. doi:10.1056/NEJMra041720. PMID 15728813. 
  9. ↑ "Systemic lupus erythematosus". The New England Journal of Medicine 365 (22): 2110–21. December 2011. doi:10.1056/NEJMra1100359. PMID 22129255. 
  10. ↑ 10.0 10.1 10.2 10.3 "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. January 2017. doi:10.1080/08820139.2016.1214962. PMID 27759478. 
  11. ↑ "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. September 1996. doi:10.1074/jbc.271.39.24063. PMID 8798643. 
  12. ↑ "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase". Nature 398 (6722): 84–90. March 1999. doi:10.1038/18050. PMID 10078535. Bibcode: 1999Natur.398...84M. 
  13. ↑ "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. December 2003. doi:10.1074/jbc.M305026200. PMID 14557276. 
  14. ↑ "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. June 1995. doi:10.1128/mcb.15.6.3171. PMID 7760813. 
  15. ↑ "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. May 1999. doi:10.1074/jbc.274.20.14229. PMID 10318843. 
  16. ↑ "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. June 1995. doi:10.1084/jem.181.6.1997. PMID 7539035. 
  17. ↑ "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. June 2001. doi:10.1042/bj3560461. PMID 11368773. 
  18. ↑ "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry 41 (34): 10732–40. August 2002. doi:10.1021/bi025554o. PMID 12186560. 
  19. ↑ "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry 269 (13): 3279–88. July 2002. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069. 
  20. ↑ "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. August 1998. doi:10.1074/jbc.273.32.20487. PMID 9685404. 

Further reading

External links



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