TYROSINE PHOSPHORYLATION PROVIDES AN EARLY AND REQUISITE SIGNAL FOR THE ACTIVATION OF NATURAL-KILLER-CELL CYTOTOXIC FUNCTION
TYROSINE PHOSPHORYLATION PROVIDES AN EARLY AND REQUISITE SIGNAL FOR THE ACTIVATION OF NATURAL-KILLER-CELL CYTOTOXIC FUNCTION
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DOI：
10.1073/pnas.88.14.6279
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发表时间：
1991-07-01
影响因子：
11.1
通讯作者：
LEIBSON, PJ
中科院分区：
文献类型：
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作者：
EINSPAHR, KJ;ABRAHAM, RT;LEIBSON, PJ
自然杀伤（NK）细胞是一种独特的淋巴细胞亚群，能够通过以下两种替代机制之一杀死恶性细胞：（i）Fc受体依赖性细胞毒性，针对抗体包被的靶标;或（ii）直接细胞介导的细胞毒性。然而，触发和随后调节NK细胞细胞毒性的分子机制尚不完全清楚。因此，我们研究了蛋白酪氨酸磷酸化在Fc受体刺激或直接肿瘤细胞接触后在克隆CD 16 +/CD 3-人NK细胞中启动的跨膜信号传导中的作用。我们报告说，Fc受体的刺激迅速诱导了一些NK细胞蛋白的酪氨酸磷酸化。这些影响发生在2分钟内，在10分钟最大，并下降到基线后60分钟。此外，Fc受体连接增加了体外蛋白激酶活性的NK细胞磷酸酪氨酸蛋白。我们还证明了NK细胞与K562肿瘤细胞的直接接触诱导了不同NK细胞磷酸酪氨酸蛋白的快速磷酸化。此外，蛋白酪氨酸激酶抑制剂除莠霉素A阻断NK细胞的细胞毒性功能，在浓度依赖性的方式。我们的研究结果表明，蛋白酪氨酸磷酸化是一个强制性的早期近端信号激活NK细胞的细胞毒功能。
Natural killer (NK) cells are a unique subpopulation of lymphocytes with the capability to kill malignant cells via one of two alternative mechanisms: (i) Fc receptor-dependent cytotoxicity against antibody-coated targets or (ii) direct cell-mediated cytotoxicity. However, the molecular mechanisms that trigger and subsequently regulate NK cell cytotoxicity are incompletely understood. We have therefore investigated the role of protein tyrosine phosphorylation in the transmembrane signaling initiated after Fc receptor stimulation or direct tumor cell contact in clonal CD16+/CD3- human NK cells. We report that stimulation of the Fc receptor rapidly induced the tyrosine phosphorylation of a number of NK cell proteins. These effects occurred within 2 min, were maximal at 10 min, and declined toward baseline after 60 min. In addition, Fc receptor ligation increased the in vitro protein kinase activity of NK cell phosphotyrosyl proteins. We have also demonstrated that direct contact of NK cells with K562 tumor cells induced the rapid phosphorylation of distinct NK cell phosphotyrosyl proteins. Furthermore, the protein-tyrosine kinase inhibitor herbimycin A blocked NK cell cytotoxic function in a concentration-dependent manner. Our results suggest that protein tyrosine phosphorylation is an obligatory early proximal signal in activating the cytotoxic function of NK cells.