Zap70

ZAP-70, or Zeta-chain-associated protein kinase 70, is a cytoplasmic protein tyrosine kinase of the Syk family that plays a central role in T cell receptor (TCR) signaling. It is recruited to the doubly phosphorylated ITAMs on the CD3 and zeta chains after TCR engagement, via its two SH2 domains, and becomes activated downstream of Lck. Once active, ZAP-70 phosphorylates key downstream substrates, notably LAT and SLP-76, enabling the assembly of the LAT signalosome and the activation of PLC-γ1, calcium flux, and downstream transcription factors such as NFAT, NF-κB, and AP-1. This signaling cascade drives T cell development, differentiation, and activation.

Expression is highest in T cells and is present at lower levels in NK cells and some innate lymphoid cells. ZAP-70 activity is tightly regulated to prevent inappropriate TCR signaling, which could lead to autoimmunity or uncontrolled T cell activation.

Clinical significance: Inherited ZAP-70 deficiency causes a T cell–focused immunodeficiency, often presenting as autosomal recessive severe combined immunodeficiency (SCID) with markedly reduced CD3+ T cells and impaired T cell responses, leading to susceptibility to viral and opportunistic infections. Management includes hematopoietic stem cell transplantation or experimental gene therapy. In oncology and hematology, ZAP-70 expression on B cells is used as a prognostic marker in chronic lymphocytic leukemia (CLL); higher ZAP-70 levels correlate with unmutated IgVH status and poorer prognosis. Pharmacologic ZAP-70 inhibitors are under investigation for autoimmune diseases and cancer, though clinical utility remains under study.

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