ZAP70 Gene

The ZAP70 gene (ZAP70 stands for "Zeta Chain of T Cell Receptor Associated Protein Kinase 70") is a protein-coding gene located on chromosome 2q11.2. Two transcript variants encoding different isoforms have been found for this gene.

The ZAP70 gene encodes an enzyme(ZAP70) that belongs to the family of protein tyrosine kinases. This plays a role in T cell development and lymphocyte activation. The ZAP70 enzyme is also important in thymocyte development. Mutations in the ZAP70 gene cause selective T cell deficiency, a severe combined immune deficiency(SCID) characterized by a selective absence of CD8-positive T cells .

ZAP70 tyrosine kinase plays an essential role in the regulation of the adaptive immune response. It regulates motility, adhesion and cytokine expression of mature T cells as well as thymocyte development. Furthermore, it also contributes to the development and activation of primary B lymphocytes (Fischer A et al. 2010).

When antigen-presenting cells (APC) activate the T cell receptor (TCR), phosphorylation leads to the recruitment of ZAP70 to the TCR component CD247/CD3Z via the ITAM motif at the plasma membrane. Subsequently, ZAP70 phosphorylates at least 2 key adapter proteins: LAT and LCP2. In turn, it recruits a large number of signaling molecules that ultimately lead to lymphokine production, T cell proliferation and differentiation.

In addition, ZAP70 controls cytoskeletal modifications, adhesion, and mobility of T lymphocytes, ensuring proper delivery of effectors to the APC.

ZAP70 further regulates both on and off T cell activation by modulating TCR expression at the T cell surface.

During thymocyte development, ZAP70 promotes survival and cell cycle progression of developing thymocytes prior to positive selection (when cells are still CD4/CD8 double negative).

Furthermore, the ZAP70-dependent signaling pathway may also contribute to the formation and activation of primary B cells through the B cell receptor (BCR).

Diseases associated with ZAP70 include:

• Immunodeficiency 48 (OMIM: 269840; Chan AC et al. 1994).
• and
• Autoimmune disease, multisystem, infantile-onset ( OMIM: 617006; Chan AY et al. 2016).

ZAP70 is expressed in chronic lymphocytic leukemia with poor prognosis and is involved in increased signaling of B-cell receptors. Therefore, expression of this protein is an ideal prognostic marker for the disease (Amin S et al 2008).

1. Amin S et al (2008) ZAP70 in chronic lymphocytic leukaemia. Int J Biochem Cell Biol. 40:1654-1658.
2. Chan AC et al (1994) ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264: 1559-1601.
3. Chan AY et al. (2016) A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J Exp Med 213: 155-165.
4. Elder ME et al (1994) Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264: 1596-1599.
5. Fischer A et al. (2010) ZAP70: a master regulator of adaptive immunity. Semin Immunopathol 32:107-116.
6. Schim van der Loeff I et al (2014) Zap70 is essential for long-term survival of naive CD8 T cells. J Immunol 193:2873-2880.