ZAP70
ZAP-70 （ zeta链相关蛋白激酶70 ）是一种通常在淋巴细胞（ T细胞、自然杀伤细胞和部分B细胞）膜表面附近表达的蛋白质。 [1]当抗原与T细胞受体（TCR）结合后，ZAP-70 会被募集是其最为人所熟知的。此外，ZAP-70还在T细胞信号传导中发挥关键作用。
1991 年，ZAP-70 在 Jurkat 细胞（一种可无限增殖的人源 T 淋巴细胞系）中被首次发现。[2]其分子量为 70 kDa ，属于蛋白-酪氨酸激酶家族，是SYK的近源同源物。SYK 和 ZAP-70 拥有共同的进化起源，从有颌脊椎动物的共同祖先中分化而来。 [3]通过比较ZAP-70在 重症联合免疫缺陷病(SCID) 患者中的表达水平， 研究人员确定了ZAP-70 在 T 细胞活化中发挥重要作用。 [2]研究发现，ZAP-70 缺陷个体的外周血中不存在功能性 T 细胞，这表明 ZAP-70 是 T 细胞活化和发育的关键组成部分。 [2]
此外，B 细胞中 ZAP-70 的表达与慢性淋巴细胞白血病(CLL) 相关。
功能
[编辑]T 细胞受体本身没有酶活性。因此，T 细胞受体通过信号分子传递来自细胞膜的信号。ZAP-70 是一种关键的胞质酪氨酸激酶，当T细胞受体被激活后，它会启动 T 细胞受体下游的信号通路。 [4]
专职性抗原呈递细胞（例如巨噬细胞、树突状细胞、朗格汉斯细胞和B细胞）通过MHC将加工过的抗原片段呈递给T细胞受体后，T淋巴细胞会被激活。激活后，TCR共受体CD4（表达于辅助性T细胞）或CD8（表达于细胞毒性T细胞）会与MHC结合，激活与共受体相关的酪氨酸激酶Lck。Lck激活后会被移动到CD3复合物附近，并磷酸化该复合物免疫受体酪氨酸激活基序（ITAMS）中的酪氨酸残基，从而形成ZAP-70的结合位点。 [5] CD3家族中最重要的成员是CD3-zeta。 ZAP-70 的SH2 结构域与 CD3-zeta 双磷酸化 的ITAMs结合，从而在空间定位上诱导 ZAP-70 磷酸化T 细胞活化跨膜蛋白连接子(linker for activation of T cells，LAT)。 [5]磷酸化的 LAT 反过来又作为停泊位点，与多种信号蛋白结合，其中包括含有 SH2 结构域 分子量为76 kDa 的白细胞蛋白 ( SLP-76 )。 [5] SLP-76 也会被 ZAP-70 磷酸化，而这一过程需要Src 家族激酶（Src family kinases）的激活。 [6] T 细胞活化的最终将调控多种基因的转录，这些基因的表达产物使 T 细胞能够分化、增殖并分泌多种细胞因子。
临床意义
[编辑]由于ZAP-70在淋巴细胞信号传导中的功能，它与多种影响淋巴细胞的疾病相关。ZAP-70的表达作为淋巴细胞存活的重要指标，与慢性淋巴细胞白血病（CLL）密切相关。 [7] CLL是一种由骨髓中B细胞过度增殖引起的癌症。
在CLL患者中，ZAP-70 水平越高，预后会越差；ZAP-70 阳性的 CLL 患者平均生存期为 8 年，而 ZAP-70 阴性的患者平均生存期则超过 25 年。低水平的ZAP-70可以使得许多患者（尤其是老年患者）放心，因为进展迟缓的病情可能令他们终生无需任何治疗。 [8]在 CLL 患者中，ZAP-70 水平越高，活化的恶性 B 细胞数量也越多。 [1]在B 细胞恶性肿瘤中 ，ZAP-70水平的提高和恶性B细胞与免疫环境之相互作用的增强密切相关，这表明 ZAP-70 在 B 细胞信号传导中发挥着复杂的作用。 [1]
在系统性红斑狼疮中，Zap-70 受体通路缺失，取而代之的是其同源物Syk。 [9]
ZAP-70 缺陷（ZAP-70 deficiency）会导致一种常染色体隐性遗传的免疫缺陷，称为联合免疫缺陷（combined immunodeficiency）。 [10]联合免疫缺陷患者的淋巴细胞计数正常，但辅助性T细胞和细胞毒性T细胞的浓度偏低。 [10]研究还发现，这些患者的淋巴细胞增殖反应异常。 [10]这表明ZAP-70 缺陷会导致T细胞活化率降低以及后续信号的传导受阻。 [10]
相互作用
[编辑]已证实 ZAP-70 与以下物质相互作用：
参见
[编辑]- Lck
- Syk
- T细胞受体
- 慢性淋巴细胞白血病
- 联合免疫缺陷（Combined immunodeficiency）
参考文献
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延伸阅读
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外部链接
[编辑]- GeneReviews/NIH/NCBI/UW entry on ZAP70-Related Severe Combined Immunodeficiency
- 醫學主題詞表（MeSH）：ZAP-70+Protein
