ZAP70 explained

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). 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.

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). 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). 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. 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.

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. Patients were also found to have irregular lymphocyte proliferation responses. These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.

Interactions

ZAP-70 has been shown to interact with:

See also

Further reading

External links

Notes and References

  1. Chen J, Moore A, Ringshausen I . ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies . Frontiers in Oncology . 10 . 595832 . 2020 . 33194762 . 7653097 . 10.3389/fonc.2020.595832 . free .
  2. Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A . ZAP-70: an essential kinase in T-cell signaling . Cold Spring Harbor Perspectives in Biology . 2 . 5 . a002279 . May 2010 . 20452964 . 2857167 . 10.1101/cshperspect.a002279 .
  3. 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 . 10.3389/fimmu.2018.01136 . 1664-3224 . 5978004 . 29881386 . free.
  4. Au-Yeung BB, Shah NH, Shen L, Weiss A . ZAP-70 in Signaling, Biology, and Disease . Annual Review of Immunology . 36 . 127–156 . April 2018 . 29237129 . 10.1146/annurev-immunol-042617-053335 . free .
  5. Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, Weiss A . ZAP-70: an essential kinase in T-cell signaling . Cold Spring Harbor Perspectives in Biology . 2 . 5 . a002279 . May 2010 . 20452964 . 2857167 . 10.1101/cshperspect.a002279 .
  6. Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C . Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes . Frontiers in Immunology . 8 . 789 . 2017 . 28736554 . 5500614 . 10.3389/fimmu.2017.00789 . free .
  7. Liu . Yini . Wang . Yangfeng . Yang . Jule . Bi . Yongyi . Wang . Hong . August 2018 . ZAP-70 in chronic lymphocytic leukemia: A meta-analysis . Clinica Chimica Acta . en . 483 . 82–88 . 10.1016/j.cca.2018.04.026 . 29680229 . 5040894.
  8. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia . The New England Journal of Medicine . 352 . 8 . 804–15 . February 2005 . 15728813 . 10.1056/NEJMra041720 .
  9. Tsokos GC . Systemic lupus erythematosus . The New England Journal of Medicine . 365 . 22 . 2110–21 . December 2011 . 22129255 . 10.1056/NEJMra1100359 .
  10. Shirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H, Farrokhi S, Frans G, Bossuyt X, Aghamohammadi A . 6 . 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 . 27759478 . 10.1080/08820139.2016.1214962 . 30518855 .
  11. Lupher ML, Reedquist KA, Miyake S, Langdon WY, Band H . 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 . 8798643 . 10.1074/jbc.271.39.24063 . free.
  12. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ . Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase . Nature . 398 . 6722 . 84–90 . March 1999 . 10078535 . 10.1038/18050 . 1999Natur.398...84M . 4411124 .
  13. Han J, Kori R, Shui JW, Chen YR, Yao Z, Tan TH . 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 . 14557276 . 10.1074/jbc.M305026200 . free .
  14. Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS . 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 . 7760813 . 230549 . 10.1128/mcb.15.6.3171 .
  15. Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, Blondel A, Acuto O . 6 . 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 . 10318843 . 10.1074/jbc.274.20.14229 . free .
  16. Thome M, Duplay P, Guttinger M, Acuto O . 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 . 7539035 . 2192070 . 10.1084/jem.181.6.1997 .
  17. Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A . 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 . 11368773 . 1221857 . 10.1042/bj3560461 .
  18. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB . 6 . Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav . Biochemistry . 41 . 34 . 10732–40 . August 2002 . 12186560 . 10.1021/bi025554o .
  19. Lindholm CK, Henriksson ML, Hallberg B, Welsh M . Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells . European Journal of Biochemistry . 269 . 13 . 3279–88 . July 2002 . 12084069 . 10.1046/j.1432-1033.2002.03008.x .
  20. Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, Telford JL, Baldari CT . 6 . 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 . 9685404 . 10.1074/jbc.273.32.20487 . free .