A New Isoform of Interleukin-3 Receptor α with Novel Differentiation Activity and High Affinity Binding Mode
A New Isoform of Interleukin-3 Receptor α with Novel Differentiation Activity and High Affinity Binding Mode
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DOI：
10.1074/jbc.m808197200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Young, Ian G.
中科院分区：
文献类型：
--
作者：
Chen, Jinglong;Olsen, Jane;Young, Ian G.
白细胞介素-3（IL-3）促进早期多能祖细胞的自我更新和分化，并参与感染诱导的造血。在这里，我们报告了对这些过程的新见解，鉴定了IL-3受体α（IL-3R α）的新亚型（SP2），存在于小鼠和人类造血细胞中，缺乏全长受体（SP1）的结构域1。β（IL-3）突变体的结合试验表明，小鼠SP2使用不同的高亲和力结合模式SP1，虽然小鼠和人的SP2和SP1可以刺激IL-3依赖性的生长。在IL-3依赖性分化模型中，人SP2和SP1对依赖于细胞环境的谱系定型或自我更新产生不同的影响，表明不同模式的胞外域结合可能调节细胞内信号传导。在多潜能因子依赖性细胞-Paterson混合物中，与SP1支持的自我更新相比，转录因子C/EBP α和PU.1以及microRNA miRNA-15 a、-223和-181a在经历SP2支持的分化的细胞中上调。同样，在M1细胞中，与SP1相比，SP2促进分化，并上调PU.1和miRNA-155和-223。这些发现表明IL-3促进的谱系定型使用与稳态造血相似的机制。SP1和SP2亚型都激活了M1细胞中的Jak 2/STAT 5、Akt和Erk 1/2信号通路，尽管SP2亚型的激活时间更长。
Interleukin-3 (IL-3) promotes both self-renewal and differentiation of early multipotential progenitors and is involved in inducible hematopoiesis in response to infections. Here we report new insights into these processes with the identification of a new isoform (SP2) of IL-3 receptor alpha(IL-3R alpha), present in mouse and human hematopoietic cells, which lacks domain 1 of the full-length receptor (SP1). Binding assays with beta(IL-3) mutants showed that mouse SP2 uses a different high affinity binding mode to SP1, although both mouse and human SP2 and SP1 can stimulate IL-3-dependent growth. In IL-3-dependent differentiation models, human SP2 and SP1 gave differential effects on lineage commitment or self-renewal dependent on the cellular context, suggesting that different modes of ectodomain binding may modulate intracellular signaling. In a multipotential factor dependent cell-Paterson mix, the transcription factors C/EBP alpha and PU.1 and microRNAs miRNA-15a, -223, and -181a were up-regulated in cells undergoing SP2-supported differentiation compared with SP1-supported self-renewal. Similarly in M1 cells, SP2 promoted differentiation compared with SP1 and gave up-regulation of PU.1 and miRNA-155 and -223. These findings suggest that IL-3-promoted lineage commitment uses similar mechanisms to those of steady-state hematopoiesis. Both the SP1 and SP2 isoforms activated the Jak2/STAT5, Akt, and Erk1/2 signaling pathways in M1 cells, although the activation was more prolonged for the SP2 isoform.