Syk regulation of phosphoinositide 3-kinase-dependent NK cell function
Syk regulation of phosphoinositide 3-kinase-dependent NK cell function
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DOI：
10.4049/jimmunol.168.7.3155
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发表时间：
2002-04-01
影响因子：
4.4
通讯作者：
Djeu, JY
中科院分区：
文献类型：
--
作者：
Jiang, K;Zhong, B;Djeu, JY
新出现的证据表明，NK激活受体使用KARAP/DAP 12、CD 3 ζ和Fc ε RI γ衔接子，这些衔接子含有基于免疫受体酪氨酸的激活基序，以介导NK通过Syk酪氨酸激酶直接裂解肿瘤细胞。NK细胞还可以使用DAP 10通过磷酸肌醇3-激酶（PI 3 K）驱动天然细胞毒性。与我们最近鉴定的控制NK细胞毒性的PI 3 K途径相反，Syk与下游效应物结合以驱动NK裂解功能的信号传导机制尚未明确定义。在表达DAP 12但几乎不表达DAP 10/NKG 2D的NK 92细胞中，我们现在表明Syk作用于PI 3 K的上游，随后导致我们先前描述的PI 3 K-> Rac 1-> PAK 1->促分裂原活化蛋白/细胞外信号调节激酶（ERK）激酶->ERK级联的特异性信号传导。肿瘤细胞结扎刺激NK 92细胞中DAP 12酪氨酸磷酸化及其与Syk的结合;还观察到Syk酪氨酸磷酸化和活化。激酶缺陷型Syk或piceatannol对Syk功能的抑制阻断了靶细胞诱导的PI 3 K、Rac 1、PAK 1、促分裂原活化蛋白/ERK激酶和ERK活化、穿孔素运动以及NK细胞毒性，表明Syk是所有这些信号传导事件的上游。证实Syk不作用于PI 3 K的下游，组成型活性PI 3 K重新激活所有下游效应子以及Syk受损NK细胞中抑制的NK细胞毒性。我们的研究结果是第一份记录Syk在控制PI 3 K依赖性天然细胞毒性中的工具作用的报告。
Emerging evidence suggests that NK-activatory receptors use KARAP/DAP12, CD3zeta, and FcepsilonRIgamma adaptors that contain immunoreceptor tyrosine-based activatory motifs to mediate NK direct lysis of tumor cells via Syk tyrosine kinase. NK cells may also use DAP10 to drive natural cytotoxicity through phosphoinositide 3-kinase (PI3K). In contrast to our recently identified PI3K pathway controlling NK cytotoxicity, the signaling mechanism by which Syk associates with downstream effectors to drive NK lytic function has not been clearly defined. In NK92 cells, which express DAP12 but little DAP10/NKG2D, we now show that Syk acts upstream of PI3K, subsequently leading to the specific signaling of the PI3K-->Rac1-->PAK1-->mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-->ERK cascade that we earlier described. Tumor cell ligation stimulated DAP12 tyrosine phosphorylation and its association with Syk in NK92 cells; Syk tyrosine phosphorylation and activation were also observed. Inhibition of Syk function by kinase-deficient Syk or piceatannol blocked target cell-induced PI3K, Rac1, PAK1, mitogen-activated protein/ERK kinase, and ERK activation, perforin movement, as well as NK cytotoxicity, indicating that Syk is upstream of all these signaling events. Confirming that Syk does not act downstream of PI3K, constitutively active PI3K reactivated all the downstream effectors as well as NK cytotoxicity suppressed in Syk-impaired NK cells. Our results are the first report documenting the instrumental role of Syk in control of PI3K-dependent natural cytotoxicity.