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
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]
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]
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]
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