ZAP70
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| Location (UCSC) | Chr 2: 97.71 – 97.74 Mb | Chr 1: 36.8 – 36.82 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of
T cell receptor
(TCR), and it plays a critical role in T cell signaling.
ZAP-70 was initially discovered in TCR-stimulated
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.
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
Syk takes its place.[13]
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000115085 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026117 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 33194762.
- ^ PMID 20452964.
- PMID 29881386.
- PMID 29237129.
- ^ PMID 20452964.
- PMID 28736554.
- S2CID 5040894.
- PMID 15728813.
- PMID 22129255.
- ^ S2CID 30518855.
- PMID 8798643.
- S2CID 4411124.
- PMID 14557276.
- PMID 7760813.
- PMID 10318843.
- PMID 7539035.
- PMID 11368773.
- PMID 12186560.
- PMID 12084069.
- PMID 9685404.
Further reading
- Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. S2CID 54326428.
- Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J (May 2007). "Structural basis for the inhibition of tyrosine kinase activity of ZAP-70". Cell. 129 (4): 735–46. S2CID 16593136.
- Orchard J, Ibbotson R, Best G, Parker A, Oscier D (December 2005). "ZAP-70 in B cell malignancies". Leukemia & Lymphoma. 46 (12): 1689–98. S2CID 30981389.
- Hamblin AD, Hamblin TJ (December 2005). "Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia". Expert Opinion on Therapeutic Targets. 9 (6): 1165–78. S2CID 20808988.
- Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. S2CID 54326428.
- Goldman F, Jensen WA, Johnson GL, Heasley L, Cambier JC (October 1994). "gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation". Journal of Immunology. 153 (7): 2905–17. S2CID 32770138.
- Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE (January 1995). "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. PMID 7528772.
- Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB (August 1995). "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. PMID 7629168.
- Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, et al. (August 1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes". Nature. 376 (6539): 435–8. S2CID 4366344.
- Mustelin T, Williams S, Tailor P, Couture C, Zenner G, Burn P, et al. (April 1995). "Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase". European Journal of Immunology. 25 (4): 942–6. S2CID 19309659.
- 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. PMID 7760813.
- Katzav S, Sutherland M, Packham G, Yi T, Weiss A (December 1994). "The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav". The Journal of Biological Chemistry. 269 (51): 32579–85. PMID 7798261.
- Schumann G, Dasgupta JD (September 1994). "Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif". International Immunology. 6 (9): 1383–92. PMID 7819147.
- Watts JD, Affolter M, Krebs DL, Wange RL, Samelson LE, Aebersold R (November 1994). "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. PMID 7961936.
- Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics. 40 (4): 300–2. S2CID 33774157.
- Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, et al. (May 1994). "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. S2CID 37831763.
- Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (June 1994). "Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase". Science. 264 (5165): 1596–9. PMID 8202712.
- Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, et al. (June 1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency". Science. 264 (5165): 1599–601. PMID 8202713.
- Wange RL, Malek SN, Desiderio S, Samelson LE (September 1993). "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. PMID 8366117.
- Huby RD, Carlile GW, Ley SC (December 1995). "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. PMID 8530437.
- Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, et al. (May 1996). "Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling". Science. 272 (5265): 1173–6. S2CID 41401787.
- Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, et al. (August 1996). "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. PMID 8702662.
External links
- GeneReviews/NIH/NCBI/UW entry on ZAP70-Related Severe Combined Immunodeficiency
- ZAP-70+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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