ZAP70 (Zeta-chain-associated protein kinase 70) (ZAP-70)

ZAP70 (Zeta-chain-associated protein kinase 70) is a cytoplasmic protein tyrosine kinase that plays an essential role in the adaptive immune response, particularly in T cell receptor (TCR) signaling. Upon TCR engagement by antigen, ZAP-70 is recruited to doubly phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3-zeta chain, which relieves its autoinhibited state and allows it to phosphorylate key adapter proteins such as LAT and LCP2 (SLP-76)[1][3]. This initiates a downstream signaling cascade leading to T cell activation, proliferation, differentiation, and cytokine production. ZAP-70 is also involved in the motility, adhesion, and cytoskeleton dynamics of T cells, ensuring effective immune synapse formation and effector function delivery[3]. During thymocyte development, ZAP-70 (along with Syk) is critical for the transition from double-negative to double-positive thymocytes; later, ZAP-70 alone is required for positive selection and lineage commitment[2]. ZAP-70 deficiency in humans and mice results in severe combined immunodeficiency (SCID) characterized by an absence of peripheral T cells, underscoring its non-redundant role in T cell development and function[1][5]. Conversely, aberrant ZAP-70 expression or activity is associated with autoimmunity and is a negative prognostic marker in chronic lymphocytic leukemia (CLL), where its presence correlates with more aggressive disease[4]. Structurally, ZAP-70 contains two N-terminal SH2 domains that bind phosphotyrosine motifs and a C-terminal kinase domain; its activation involves phosphorylation by Src family kinases and conformational changes that release autoinhibition[1][7][9]. ZAP-70 is considered a promising therapeutic target for modulating pathological T cell responses, although no ZAP-70-specific drugs are yet approved for clinical use[5]. Its restricted expression in immune cells and central role in TCR signaling make it attractive for immune modulation, but also pose challenges for safety and specificity in drug development.

Other names

Zeta-associated protein of 70 kDaZeta-chain-associated protein kinase 70Tyrosine-protein kinase ZAP-70

Tyrosine kinase inhibitors (theoretical), allosteric inhibitors targeting regulatory domains (research context); exact mechanisms for tested compounds are not specified in reviewed literature