Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)
Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244)
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DOI：
10.1182/blood-2004-09-3796
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Watzl, C
中科院分区：
文献类型：
--
作者：
Eissmann, P;Beauchamp, L;Watzl, C
2B 4（CD 244）的触发可以诱导自然杀伤（NK）细胞活化，共刺激，甚至抑制NK细胞活性。在这里，我们研究了2B 4产生的不同信号的分子基础。我们发现，第一个免疫受体酪氨酸为基础的开关基序（ITSM）内的胞质尾的2B 4是足够的2B 4介导的NK细胞活化，而第三ITSM可以负面影响2B 4信号。我们进一步鉴定了与2B 4相关的信号分子。信号淋巴细胞活化分子相关蛋白（SAP）可以以磷酸化依赖性方式与2B 4的所有4种ITSM结合。磷酸化的第三ITSM可以另外募集磷酸酶SHP-1、SHP-2、SHIP和抑制性激酶Csk。SAP作为2B 4和这些负调控分子之间相互作用的抑制剂，解释了2B 4如何在缺乏功能性SAP的情况下抑制NK细胞活化，如发生在X连锁淋巴细胞增生综合征（XLP）患者的细胞中。最近，提出了SAP的另一种功能：SAP可以将激酶Fyn募集到SLAM（CD 150）免疫受体。我们现在表明，Fyn也可以与磷酸化的2B 4。最后，我们证明Fyn和Csk都可以磷酸化2B 4，这表明2B 4磷酸化的可能机制。(c)2005年，美国血液学会。
Triggering of 2B4 (CD244) can induce natural killer (NK)-cell activation, costimulation, or even inhibition of NK-cell activity. Here, we investigate the molecular basis for the different signals generated by 2B4. We show that the first immunoreceptor tyrosine-based switch motif (ITSM) within the cytoplasmic tail of 2B4 is sufficient for 2B4-mediated NK-cell activation, whereas the third ITSM can negatively influence 2B4 signaling. We further identify signaling molecules that associate with 2B4. Signaling lymphocyte activation molecule-associated protein (SAP) can bind to all 4 ITSMs of 2B4 in a phosphorylation-dependent manner. The phosphorylated third ITSM can additionally recruit the phosphatases SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk. SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP, as occurs in cells from patients with X-linked lymphoproliferative syndrome (XLP). Recently, another function for SAP was proposed: SAP can recruit the kinase Fyn to the SLAM (CD150) immune receptor. We now show that Fyn can also associate with phosphorylated 2B4. Finally, we demonstrate that Fyn and Csk can both phosphorylate 2B4, suggesting a possible mechanism of 2B4 phosphorylation. (c) 2005 by The American Society of Hematology.