The structure, regulation, and function of ZAP-70.
The tyrosine ZAP-70 (zeta-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.
Au-Yeung
Byron B
BB
Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143-0795, USA.
Deindl
Sebastian
S
Hsu
Lih-Yun
LY
Palacios
Emil H
EH
Levin
Susan E
SE
Kuriyan
John
J
Weiss
Arthur
A
D000818:Animals; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase