ZAP70
ZAP-70 （ zeta鏈相關蛋白激酶70 ）是一種通常在淋巴細胞（ T細胞、自然殺傷細胞和部分B細胞）膜表面附近表達的蛋白質。 [1]當抗原與T細胞受體（TCR）結合後，ZAP-70 會被募集是其最為人所熟知的。此外，ZAP-70還在T細胞信號傳導中發揮關鍵作用。
1991 年，ZAP-70 在 Jurkat 細胞（一種可無限增殖的人源 T 淋巴細胞系）中被首次發現。[2]其分子量為 70 kDa ，屬於蛋白-酪氨酸激酶家族，是SYK的近源同源物。SYK 和 ZAP-70 擁有共同的進化起源，從有頜脊椎動物的共同祖先中分化而來。 [3]通過比較ZAP-70在 重症聯合免疫缺陷病(SCID) 患者中的表達水平， 研究人員確定了ZAP-70 在 T 細胞活化中發揮重要作用。 [2]研究發現，ZAP-70 缺陷個體的外周血中不存在功能性 T 細胞，這表明 ZAP-70 是 T 細胞活化和發育的關鍵組成部分。 [2]
此外，B 細胞中 ZAP-70 的表達與慢性淋巴細胞白血病(CLL) 相關。
功能
[編輯]T 細胞受體本身沒有酶活性。因此，T 細胞受體通過信號分子傳遞來自細胞膜的信號。ZAP-70 是一種關鍵的胞質酪氨酸激酶，當T細胞受體被激活後，它會啟動 T 細胞受體下游的信號通路。 [4]
專職性抗原呈遞細胞（例如巨噬細胞、樹突狀細胞、朗格漢斯細胞和B細胞）通過MHC將加工過的抗原片段呈遞給T細胞受體後，T淋巴細胞會被激活。激活後，TCR共受體CD4（表達於輔助性T細胞）或CD8（表達於細胞毒性T細胞）會與MHC結合，激活與共受體相關的酪氨酸激酶Lck。Lck激活後會被移動到CD3複合物附近，並磷酸化該複合物免疫受體酪氨酸激活基序（ITAMS）中的酪氨酸殘基，從而形成ZAP-70的結合位點。 [5] CD3家族中最重要的成員是CD3-zeta。 ZAP-70 的SH2 結構域與 CD3-zeta 雙磷酸化 的ITAMs結合，從而在空間定位上誘導 ZAP-70 磷酸化T 細胞活化跨膜蛋白連接子(linker for activation of T cells，LAT)。 [5]磷酸化的 LAT 反過來又作為停泊位點，與多種信號蛋白結合，其中包括含有 SH2 結構域 分子量為76 kDa 的白血球蛋白 ( SLP-76 )。 [5] SLP-76 也會被 ZAP-70 磷酸化，而這一過程需要Src 家族激酶（Src family kinases）的激活。 [6] T 細胞活化的最終將調控多種基因的轉錄，這些基因的表達產物使 T 細胞能夠分化、增殖並分泌多種細胞因子。
臨床意義
[編輯]由於ZAP-70在淋巴細胞信號傳導中的功能，它與多種影響淋巴細胞的疾病相關。ZAP-70的表達作為淋巴細胞存活的重要指標，與慢性淋巴細胞白血病（CLL）密切相關。 [7] CLL是一種由骨髓中B細胞過度增殖引起的癌症。
在CLL患者中，ZAP-70 水平越高，預後會越差；ZAP-70 陽性的 CLL 患者平均生存期為 8 年，而 ZAP-70 陰性的患者平均生存期則超過 25 年。低水平的ZAP-70可以使得許多患者（尤其是老年患者）放心，因為進展遲緩的病情可能令他們終生無需任何治療。 [8]在 CLL 患者中，ZAP-70 水平越高，活化的惡性 B 細胞數量也越多。 [1]在B 細胞惡性腫瘤中 ，ZAP-70水平的提高和惡性B細胞與免疫環境之相互作用的增強密切相關，這表明 ZAP-70 在 B 細胞信號傳導中發揮著複雜的作用。 [1]
在系統性紅斑狼瘡中，Zap-70 受體通路缺失，取而代之的是其同源物Syk。 [9]
ZAP-70 缺陷（ZAP-70 deficiency）會導致一種常染色體隱性遺傳的免疫缺陷，稱為聯合免疫缺陷（combined immunodeficiency）。 [10]聯合免疫缺陷患者的淋巴細胞計數正常，但輔助性T細胞和細胞毒性T細胞的濃度偏低。 [10]研究還發現，這些患者的淋巴細胞增殖反應異常。 [10]這表明ZAP-70 缺陷會導致T細胞活化率降低以及後續信號的傳導受阻。 [10]
相互作用
[編輯]已證實 ZAP-70 與以下物質相互作用：
參見
[編輯]- Lck
- Syk
- T細胞受體
- 慢性淋巴細胞白血病
- 聯合免疫缺陷（Combined immunodeficiency）
參考文獻
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延伸閱讀
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外部連結
[編輯]- GeneReviews/NIH/NCBI/UW entry on ZAP70-Related Severe Combined Immunodeficiency
- 醫學主題詞表（MeSH）：ZAP-70+Protein
