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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 A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
,
natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
, and a subset of
B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
). It is most prominently known to be recruited upon antigen binding to the
T cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding ...
(TCR), and it plays a critical role in T cell signaling. ZAP-70 was initially discovered in TCR-stimulated
Jurkat cells Jurkat cells are an immortalized line of human T lymphocyte cells that are used to study acute T cell leukemia, T cell signaling, and the expression of various chemokine receptors susceptible to viral entry, particularly HIV. Jurkat cells can pr ...
, an immortal line of human T lymphocytes, in 1991. Its molecular weight is 70
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
, and it is a member of the protein-
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
family and is a close homolog of
SYK Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
. SYK and ZAP70 share a common
evolutionary Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
origin and split from a
common ancestor Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. All living beings are in fact descendants of a unique ancestor commonly referred to as the last universal comm ...
in the jawed vertebrates. The importance of ZAP-70 in T cell activation was determined when comparing ZAP-70 expression in patients with SCID (
severe combined immunodeficiency Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in diffe ...
). 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. T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e.
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
,
dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
,
Langerhans cells A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in t ...
and
B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
) via the MHC. Upon this activation, the TCR co-receptor CD4 (expressed on
T helper cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
) or CD8 (expressed on
cytotoxic T cells A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...
) binds to the MHC, activating the co-receptor associated tyrosine kinase
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
. 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. The most important member of the CD3 family is
CD3-zeta T-cell surface glycoprotein CD3 zeta chain also known as T-cell receptor T3 zeta chain or CD247 (Cluster of Differentiation 247) is a protein that in humans is encoded by the ''CD247'' gene. Some older literature mention a similar protein called " ...
, to which ZAP-70 binds (hence the abbreviation). The tandem
SH2-domains The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphory ...
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 The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a protein involved in the T-cell antigen receptor signal transduction pathway which in humans is encoded by the ''LAT'' gene. Alternative splicing results ...
(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 Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell recepto ...
). SLP-76 is also phosphorylated by ZAP-70, which requires its activation by
Src family kinases Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs i ...
. 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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
.


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). 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. 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 Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
, the Zap-70 receptor pathway is missing and the homolog
Syk Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
takes its place. ZAP-70 deficiency results in a form of autosomal recessive
immune deficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
named
combined immunodeficiency Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity. This category includes conditions such ...
. 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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
Cbl gene ''Cbl'' (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a numbe ...
, *
Drebrin-like Drebrin-like protein is a protein that in humans is encoded by the ''DBNL'' gene. Interactions Drebrin-like has been shown to interact with Cyclin-dependent kinase 4, MAP4K1 and ZAP-70 ZAP-70 (Zeta-chain-associated protein kinase 70) is a pr ...
, *
FYN Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
, *
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
, *
LAT Lat or LAT may refer to: Places * Lat, Fuman, village in Gilan Province, Iran * Lat, Rasht, village in Gilan Province, Iran * Lat, Mazandaran, village in Iran * Lat-e Disar, village in Mazandaran Province, Iran * Lat, Qazvin, village in I ...
, * SHB, and *
SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...
.


See also

*
Lck Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
*
Syk Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene. Function SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
*
T cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding ...
* Chronic lymphocytic leukemia *
Combined immunodeficiency Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity. This category includes conditions such ...


References


Further reading

* * * * * * * * * * * * * * * * * * * * * *


External links


GeneReviews/NIH/NCBI/UW entry on ZAP70-Related Severe Combined Immunodeficiency
* {{DEFAULTSORT:Zap-70 Tyrosine kinases