• ZAP-70;
  • signal transduction;
  • T-cell receptor;
  • pre-TCR signals;
  • autoinhibition;
  • ITAM

Summary:  The tyrosine ZAP-70 (ζ-associated protein of 70 kDa) kinase plays a critical role in activating many downstream signal transduction pathways in T cells following T-cell receptor (TCR) engagement. The importance of ZAP-70 is evidenced by the severe combined immunodeficiency that occurs in ZAP-70-deficient mice and humans. In this review, we describe recent analyses of the ZAP-70 crystal structure, revealing a complex regulatory mechanism of ZAP-70 activity, the differential requirements for ZAP-70 and spleen tyrosine kinase (SyK) in early T-cell development, as well as the role of ZAP-70 in chronic lymphocytic leukemia and autoimmunity. Thus, the critical importance of ZAP-70 in TCR signaling and its predominantly T-cell-restricted expression pattern make ZAP-70 an attractive drug target for the inhibition of pathological T-cell responses in disease.