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
- Chan AC, Iwashima M, Turck CW, Weiss A . ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain . Cell . 71 . 4 . 649–62 . November 1992 . 1423621 . 10.1016/0092-8674(92)90598-7 . 54326428 .
- Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J . Structural basis for the inhibition of tyrosine kinase activity of ZAP-70 . Cell . 129 . 4 . 735–46 . May 2007 . 17512407 . 10.1016/j.cell.2007.03.039 . 16593136 . free .
- Orchard J, Ibbotson R, Best G, Parker A, Oscier D . ZAP-70 in B cell malignancies . Leukemia & Lymphoma . 46 . 12 . 1689–98 . December 2005 . 16263570 . 10.1080/09638280500260079 . 30981389 .
- Hamblin AD, Hamblin TJ . Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia . Expert Opinion on Therapeutic Targets . 9 . 6 . 1165–78 . December 2005 . 16300468 . 10.1517/14728222.9.6.1165 . 20808988 .
- Chan AC, Iwashima M, Turck CW, Weiss A . ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain . Cell . 71 . 4 . 649–62 . November 1992 . 1423621 . 10.1016/0092-8674(92)90598-7 . 54326428 .
- Goldman F, Jensen WA, Johnson GL, Heasley L, Cambier JC . gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation . Journal of Immunology . 153 . 7 . 2905–17 . October 1994 . 10.4049/jimmunol.153.7.2905 . 7522245 . 32770138 . free .
- Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE . 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 . January 1995 . 7528772 . 2191847 . 10.1084/jem.181.1.375 .
- Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB . 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 . August 1995 . 7629168 . 10.1074/jbc.270.31.18428 . free.
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- 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 .
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- Schumann G, Dasgupta JD . Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif . International Immunology . 6 . 9 . 1383–92 . September 1994 . 7819147 . 10.1093/intimm/6.9.1383 .
- Watts JD, Affolter M, Krebs DL, Wange RL, Samelson LE, Aebersold R . 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 . November 1994 . 10.1016/S0021-9258(18)43911-7 . 7961936 . free .
- Ku G, Malissen B, Mattei MG . Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans . Immunogenetics . 40 . 4 . 300–2 . 1994 . 8082894 . 10.1007/BF00189976 . 33774157 .
- Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, Clark EA, Weiss A . 6 . 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 . May 1994 . 10.4049/jimmunol.152.10.4758 . 8176201 . 37831763 .
- Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG . Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase . Science . 264 . 5165 . 1596–9 . June 1994 . 8202712 . 10.1126/science.8202712 . 1994Sci...264.1596E .
- Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A . 6 . ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency . Science . 264 . 5165 . 1599–601 . June 1994 . 8202713 . 10.1126/science.8202713 . 1994Sci...264.1599C .
- Wange RL, Malek SN, Desiderio S, Samelson LE . 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 . September 1993 . 10.1016/S0021-9258(19)36584-6 . 8366117 . free .
- Huby RD, Carlile GW, Ley SC . 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 . December 1995 . 8530437 . 10.1074/jbc.270.51.30241 . free .
- Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC, Thomas ML . 6 . Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling . Science . 272 . 5265 . 1173–6 . May 1996 . 8638162 . 10.1126/science.272.5265.1173 . 1996Sci...272.1173P . 41401787 .
- Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR . 6 . 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 . August 1996 . 8702662 . 10.1074/jbc.271.33.19641 . free .
External links
Notes and References
- 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 .
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- 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 .
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