ZAP70

ZAP70
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4XZ0, 1FBV, 1M61, 1U59, 2CBL, 2OQ1, 2OZO, 2Y1N, 3ZNI, 4A4B, 4A4C, 4K2R, 4XZ1
Identifiers
Aliases	ZAP70, SRK, STCD, STD, TZK, ZAP-70, zeta chain of T cell receptor associated protein kinase 70kDa, zeta chain of T cell receptor associated protein kinase 70, zeta chain of T-cell receptor associated protein kinase 70, IMD48, ADMIO2
External IDs	OMIM: 176947 MGI: 99613 HomoloGene: 839 GeneCards: ZAP70
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q11.2 Start 97,713,576 bp[1] End 97,739,862 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 B|1 15.41 cM Start 36,800,879 bp[2] End 36,821,899 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lymph node blood spleen appendix thymus gallbladder upper lobe of left lung bone marrow cells thymus right lobe of liver Top expressed in thymus blood left lobe of liver morula subcutaneous adipose tissue Purkinje cell pharynx duodenum spermatid visual cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity non-membrane spanning protein tyrosine kinase activity kinase activity protein binding protein tyrosine kinase activity signaling receptor binding ATP binding phosphotyrosine residue binding Cellular component cytoplasm cytosol membrane cell-cell junction extrinsic component of cytoplasmic side of plasma membrane plasma membrane T cell receptor complex immunological synapse membrane raft Biological process positive regulation of T cell differentiation T cell migration positive regulation of calcium-mediated signaling intracellular signal transduction adaptive immune response phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway immune system process T cell aggregation beta selection negative thymic T cell selection protein phosphorylation B cell activation T cell differentiation immune response positive thymic T cell selection peptidyl-tyrosine autophosphorylation protein autophosphorylation peptidyl-tyrosine phosphorylation innate immune response T cell receptor signaling pathway thymic T cell selection positive regulation of alpha-beta T cell differentiation T cell activation regulation of cell population proliferation positive regulation of alpha-beta T cell proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7535 22637 Ensembl ENSG00000115085 ENSMUSG00000026117 UniProt P43403 P43404 RefSeq (mRNA) NM_001079 NM_207519 NM_001378594 NM_009539 NM_001289612 NM_001289765 NM_001289766 RefSeq (protein) NP_001070 NP_997402 NP_001365523 NP_001276541 NP_001276694 NP_001276695 NP_033565 Location (UCSC) Chr 2: 97.71 – 97.74 Mb Chr 1: 36.8 – 36.82 Mb PubMed search [3] [4]
Wikidata
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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).^[5] 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.^[6] 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. ^[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. 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.^[9] 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).^[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 systemic lupus erythematosus, the Zap-70 receptor pathway is missing and the homolog Syk takes its place.^[13]

ZAP-70 deficiency results in a form of autosomal recessive 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

• Lck
• Syk
• T cell receptor
• Chronic lymphocytic leukemia
• Combined immunodeficiency

References

Further reading

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)