NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following kit activation and FcεRI aggregation
NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following kit activation and FcεRI aggregation
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DOI：
10.1182/blood-2003-08-2769
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发表时间：
2004-07-01
期刊：
影响因子：
20.3
通讯作者：
Gilfillan, AM
中科院分区：
文献类型：
--
作者：
Tkaczyk, C;Horejsi, V;Gilfillan, AM
高亲和力的免疫球蛋白E受体(FcepsilonRI)聚集在肥大细胞表面导致脱颗粒，这种反应因干细胞因子(SCF)与其受体试剂盒结合而增强。我们观察到与FcepsilonRI介导的人肥大细胞(HuMCs)激活相关的主要初始信号事件之一是25-30 kDa蛋白质的快速酪氨酸磷酸化。该蛋白的磷酸化也被观察到对SCF的反应。该蛋白被鉴定为非T细胞激活连接物(NTAL)，与活化T细胞连接物(LAT)相似的接头分子。与FcepsilonRI反应不同，SCF在没有检测到LAT磷酸化的情况下诱导了NAT的磷酸化。当SCF和抗原同时加入时，SCF对NAT的磷酸化有明显的协同作用，但SCF不能增强FcepsilonRI聚集诱导的LAT的磷酸化。FcepsilonRI和SCF介导的NTAL磷酸化似乎分别受Src激酶和/或Kit激酶的不同调控。通过沉默HuMCs中的RNA寡核苷酸来减少NTAL的表达，导致Kit和FcepsilonRI介导的脱颗粒减少。因此，NTAL似乎是由这些受体启动的信号通路之间的重要联系，最终导致肥大细胞脱颗粒。
Aggregation of high-affinity receptors for immunoglobulin E (FcepsilonRI) on the surface of mast cells results in degranulation, a response that is potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed that one of the major initial signaling events associated with FcepsilonRI-mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphorylation of a protein of 25 to 30 kDa. The phosphorylation of this protein was also observed in response to SCF. This protein was identified as non-T-cell activation linker (NTAL), an adaptor molecule similar to linker for activated T cells (LAT). Unlike the FcepsilonRI response, SCF induced NTAL phosphorylation in the absence of detectable LAT phosphorylation. When SCF and antigen were added concurrently, there was a marked synergistic effect on NTAL phosphorylation, however, SCF did not enhance the phosphorylation of LAT induced by FcepsilonRI aggregation. FcepsilonRI- and SCF-mediated NTAL phosphorylation appear to be differentially regulated by Src kinases and/or Kit kinase, respectively. Diminution of NTAL expression by silencing RNA oligonucleotides in HuMCs resulted in a reduction of both Kit- and FcepsilonRI-mediated degranulation. NTAL, thus, appears to,be an important link between the signaling Pathways that are initiated by these receptors, culminating in mast cell degranulation.