Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling
Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling
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DOI：
10.1182/blood.v93.12.4354.412k30_4354_4364
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发表时间：
1999-06-15
期刊：
影响因子：
20.3
通讯作者：
Barber, DL
中科院分区：
文献类型：
--
作者：
Ho, JMY;Beattie, BK;Barber, DL
为了研究组成型Janus激酶信号传导，在ets转录因子TEL的尖域和胞质酪氨酸激酶Jak 2之间产生嵌合蛋白。研究了这些蛋白对白细胞介素3（IL-3）依赖的造血细胞系Ba/F3增殖的影响。将TEL融合到Jak 2的功能激酶（JH 1）结构域导致Ba/F3细胞转化为因子非依赖性。重要的是，TEL与Jak 2假激酶（JH 2）结构域或激酶失活的Jak 2 JH 1结构域的融合对Ba/F3细胞的IL-3依赖性增殖没有影响。活性TEL-Jak 2构建体（由Jak 2 JH 1或Jak 2 JH 2 + JH 1结构域融合体组成）是组成性酪氨酸磷酸化的，但不影响内源性Jak 1、Jak 2或Jak 3的磷酸化。TEL-Jak 2激活导致Stat 1、Stat 3和Stat 5的组成性酪氨酸磷酸化，如通过使用激活特异性抗体检测磷酸化和通过电泳迁移率变动测定中每种蛋白与优先GAS序列的结合所确定的。阐明TEL Jak 2激活下游的信号事件可能提供对由这种致癌融合蛋白介导的白血病发生机制的深入了解。(C)1999年，美国血液学会。
To study constitutive Janus kinase signaling, chimeric proteins were generated between the pointed domain of the ets transcription factor TEL and the cytosolic tyrosine kinase Jak2. The effects of these proteins on interleukin-3 (IL-3)-dependent proliferation of the hematopoietic cell line, Ba/F3, were studied, Fusion of TEL to the functional kinase (JH1) domain of Jak2 resulted in conversion of Ba/F3 cells to factor-independence. Importantly, fusion of TEL to the Jak2 pseudokinase (JH2) domain or a kinase-inactive Jak2 JH1 domain had no effect on IL-3-dependent proliferation of Ba/F3 cells. Active TEL-Jak2 constructs (consisting of either Jak2 JH1 or Jak2 JH2+JH1 domain fusions) were constitutively tyrosine-phosphorylated but did not affect phosphorylation of endogeneous Jak1, Jak2, or Jak3. TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays. Elucidation of signaling events downstream of TEL Jak2 activation may provide insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein. (C) 1999 by The American Society of Hematology.