Historical Background
Since its initial discovery in 1992 by the Weiss group, ZAP-70 (ζ-associated protein of 70 kDa) has attracted significant attention as a central player in the early steps of T-cell antigen receptor (TCR) signaling during T-cell development and activation.
TCR engagement results in a dynamic phosphorylation cascade primarily regulated by two different families of protein tyrosine kinases (PTKs), the Src-( Sa RComa) and the Syk/ZAP-70 PTKs. When the TCR αβ heterodimer binds peptide-MHC (pMHC), the noncovalently associated CD3ζζ homodimer is phosphorylated by the Src kinase Lck on two specific tyrosine residues located in the consensus sequence known as immunoreceptor tyrosine-based activation motif (ITAM). These motifs, present in the cytosolic tail of all invariant signaling subunits of the TCR complex (CD3γ, δ, ε and η/ζ chains), consist of the consensus amino acid sequence [(D/E)xxYxxI/Lx(6–8)YxxI/L]. ZAP-70 binds...
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, et al. The structure, regulation, and function of ZAP-70. Immunol Rev. 2009;228(1):41–57.
Bene MC. What is ZAP-70? Cytometry B Clin Cytom. 2006;70(4):204–8.
Ensafi AA, Amini M, Rezaei B, Talebi M. A novel diagnostic biosensor for distinguishing immunoglobulin mutated and unmutated types of chronic lymphocytic leukemia. Biosens Bioelectron. 2016;77:409–15.
Evans R, Lellouch AC, Svensson L, McDowall A, Hogg N. The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes. Blood. 2011;117(12):3331–42.
Ferjeni Z, Bouzid D, Fouratia H, Stayoussefa M, Abida O, Kammoun T, et al. Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population-family based association study. Immunol Lett. 2015;163:1–7.
Fischer A, Picard C, Chemin K, Dogniaux S, le Deist F, Hivroz C. ZAP-70: a master regulator of adaptive immunity. Semin Immunopathol. 2010;32(2):107–16.
Goodfellow H, Frushicheva MP, Q J, Cheng DA, Kadlecek TA, Cantor AJ, et al. The catalytic activity of the kinase ZAP70 mediates basal signaling and negative feedback of T cell receptor pathway. Sci Signal. 2015;8(377):ra49. https://doi.org/10.1126/scisignal.2005596.
Humphrey MB, Lanier LL, Nakamura MC. Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunol Rev. 2005;208:50–65.
Ivanova E, Carpino N. Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217. Mol Immunol. 2016;73:19–28.
Jin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC, Rynkiewicz MJ, et al. The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine implications for the design of selective inhibitors. J Biol Chem. 2004;279(41):42818–25.
Mahon RN, Sande OJ, Rojas RE, Levine AD, Clifford V, Harding CV, Boom WH. Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell Immunol. 2012;275(1–2):98–105.
Montserrat E. New prognostic markers in CLL. Hematol Am Soc Hematol Educ Program. 2006;1:279–84.
Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, et al. Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation. J Biol Chem. 1998;273(32):20487–93.
Pezzicoli A, Baldari CT. ZAP-70. AfCS Nat Molecule Pages. 2005; https://doi.org/10.1038/mp.a002396.01.
Siggs OM, Miosge LA, Yates AL, Kucharska EM, Sheahan D, Brdicka T, et al. Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity. 2007;27:912–26.
Smith-Garvin JE, Koretzky GA, MS J. T cell activation. Annu Rev Immunol. 2009;27:591–619.
Sood S, Brownlie RJ, Garcia C, Cowan G, Salmond RJ, Sakaguchi S, et al. Loss of the protein tyrosine phosphatase PTPN22 reduces mannan-induced autoimmune arthritis in SKG mice. J Immunol. 2016;197(2):429–40.
Thomas R, Turner M, Cope AP. High avidity autoreactive T cells with a low signaling capacity through the T-cell receptor: central to rheumatoid arthritis pathogenesis? Arthritis Res Ther. 2008;10(4):210.
Visperas PR, Winger JA, Horton TM, Shah NH, Aum DJ, Tao A, et al. Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding. Biochem J. 2015;465(1):149–61.
Wang H, Kadlecek TA, Au-Yeung BB, Goodfellow HE, Hsu LY, Freedman TS, et al. ZAP-70: an essential kinase in T-cell signaling. Cold Spring Harb Perspect Biol. 2010;2(5):a002279.
Wiestner A. More ZAP-70 for chronic lymphocytic leukemia (CLL). Blood. 2005;105(5):1839–40.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this entry
Cite this entry
Galgano, D., Ferro, M., Giommoni, N., Baldari, C.T. (2018). Zap-70. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_83
Download citation
DOI: https://doi.org/10.1007/978-3-319-67199-4_83
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67198-7
Online ISBN: 978-3-319-67199-4
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences