Au-Yeung Byron B, Deindl Sebastian, Hsu Lih-Yun, Palacios Emil H, Levin Susan E, Kuriyan John, Weiss Arthur
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.
Immunol Rev. 2009 Mar;228(1):41-57. doi: 10.1111/j.1600-065X.2008.00753.x.
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.
酪氨酸ZAP-70（70 kDa的ζ相关蛋白）激酶在T细胞受体（TCR）结合后激活T细胞中许多下游信号转导途径方面发挥着关键作用。ZAP-70缺陷的小鼠和人类中出现的严重联合免疫缺陷证明了ZAP-70的重要性。在这篇综述中，我们描述了对ZAP-70晶体结构的最新分析，揭示了ZAP-70活性的复杂调节机制、早期T细胞发育中ZAP-70和脾酪氨酸激酶（SyK）的不同需求，以及ZAP-70在慢性淋巴细胞白血病和自身免疫中的作用。因此，ZAP-70在TCR信号传导中的关键重要性及其主要受T细胞限制的表达模式使ZAP-70成为抑制疾病中病理性T细胞反应的有吸引力的药物靶点。
