ZAP-70, or Zeta-chain associated protein kinase 70, is a protein found primarily within the immune system. It is predominantly expressed in T cells and natural killer cells, types of white blood cells. ZAP-70 serves a role in the body’s immune response by acting as a signaling molecule.
ZAP-70’s Role in T-Cell Activation
ZAP-70 functions as a tyrosine kinase, an enzyme that adds phosphate groups to specific tyrosine amino acids on other proteins. This action is a step in cellular signaling, particularly within T-cells. When a T-cell encounters a foreign substance, such as a pathogen, an antigen-presenting cell displays fragments of that substance to the T-cell receptor (TCR) on the T-cell’s surface.
This interaction triggers a series of events, beginning with the activation of another enzyme called Lck, associated with the T-cell’s co-receptors (CD4 or CD8). Lck then phosphorylates specific sites on the CD3 zeta chain, a part of the TCR complex. These phosphorylated sites create docking points for ZAP-70, allowing it to bind to the TCR complex.
Upon binding, ZAP-70 is activated by Lck phosphorylation. Activated ZAP-70 then phosphorylates other downstream signaling proteins, such as LAT and SLP-76. These scaffolding proteins, once phosphorylated, recruit additional molecules, initiating a cascade that ultimately leads to the T-cell’s activation, proliferation, and differentiation into effector cells capable of neutralizing the perceived threat. This cascade enables T-cells to effectively recognize and respond to invaders, forming a protective adaptive immune response.
ZAP-70 and Immune System Conditions
Dysregulation of ZAP-70 activity can lead to various immune system conditions, either through insufficient or excessive function. A deficiency in ZAP-70, often due to genetic mutations, results in a severe form of immunodeficiency known as ZAP-70-related combined immunodeficiency (CID). Individuals with this condition present with recurrent bacterial, viral, and opportunistic infections. Their T-cells, particularly CD8+ T-cells, are either absent or non-functional.
Without proper ZAP-70 function, T-cells cannot activate correctly, leading to a compromised immune system similar to severe combined immunodeficiency (SCID). This can manifest as severe lower-respiratory infections, oral candidiasis, and a failure to thrive. Hematopoietic stem cell transplantation is a common treatment option, as affected children often do not survive past their second year without it.
Conversely, overactivity or misregulation of ZAP-70 can contribute to autoimmune diseases. In these conditions, T-cells may mistakenly attack the body’s own healthy tissues, as seen in certain forms of arthritis or lupus.
ZAP-70 in Cancer
ZAP-70 also holds significance in the context of certain cancers, particularly as a prognostic marker. In Chronic Lymphocytic Leukemia (CLL), the presence or absence of ZAP-70 protein in cancerous B-cells provides important information. CLL is characterized by the overproduction of immature white blood cells in the bone marrow.
Patients with CLL who have higher levels of ZAP-70 expression in their cancer cells face a less favorable prognosis and a more aggressive form of the disease. For instance, CLL patients positive for ZAP-70 may have an average survival of approximately 8 years, whereas those who are negative for ZAP-70 might have an average survival exceeding 25 years. ZAP-70 expression helps distinguish between more aggressive and less aggressive forms of CLL, assisting doctors in predicting the disease’s course.
While ZAP-70 is not typically considered a direct cause of cancer, its presence in CLL cells is associated with enhanced B-cell receptor signaling, suggesting a role in promoting the cancer’s progression. This information allows clinicians to guide treatment decisions, potentially leading to more intensive therapies for patients with ZAP-70 positive CLL. Therefore, ZAP-70 serves as a valuable biomarker, providing insights into the likely behavior of the cancer and informing personalized treatment strategies.