An epidermal growth factor receptor Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells
An epidermal growth factor receptor Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells
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DOI：
10.1074/jbc.271.32.19483
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发表时间：
1996-08-09
影响因子：
4.8
通讯作者：
Miura, O
中科院分区：
文献类型：
--
作者：
Nakamura, N;Chin, H;Miura, O
酪氨酸激酶的Jak家族和转录因子的Stat家族已经涉及来自造血生长因子受体的转导信号。为了探索Jak家族成员Jak 2在造血细胞生长信号传导中所起的作用，我们构建了一个嵌合cDNA，编码与表皮生长因子（EGF）受体（EGFR）的细胞外和跨膜区连接的Jak 2酪氨酸激酶结构域，并在白细胞介素（IL）-3依赖性细胞系32 D中表达嵌合体。当剥夺IL-3时，EGF阻止转染细胞的凋亡，诱导剂量依赖性增殖，并支持长期生长。EGF刺激的转染诱导EGFR/Jak 2嵌合体和Stat 5的剂量依赖性酪氨酸磷酸化，这与细胞增殖的EGF剂量依赖性相关。另一方面，EGF不诱导参与细胞因子受体信号传导的其他因子的酪氨酸磷酸化，包括IL-3受体β亚基、Jak激酶、Stat 5以外的Stat蛋白、Shc、Syp和促分裂原活化蛋白激酶。这些结果表明，Jak 2的激活可能足以通过激活Stat 5通路或先前未鉴定的信号通路来转导造血细胞中的生长信号。此外，由于EGF诱导EGFR的同源二聚化以激活其酪氨酸激酶活性，因此本研究显示EGFR/Jak 2嵌合体的EGF依赖性激活，这意味着Jak 2也可能通过同源二聚化而被激活。
The Jak family of tyrosine kinases and the Stat family of transcription factors have been implicated in transducing signals from the hematopoietic growth factor receptors. To explore the role played by a member of the Jak family, Jak2, in hematopoietic cell growth signaling, we constructed a chimeric cDNA coding for the Jak2 tyrosine kinase domain linked to the extracellular and transmembrane regions of the epidermal growth factor (EGF) receptor (EGFR) and expressed the chimera in an interleukin (IL)-3-dependent cell line, 32D. When deprived of IL-3, EGF prevented apoptosis of the transfected cells, induced dose dependent proliferation, and supported long-term growth. EGF stimulation of the transfectants induced dose-dependent tyrosine phosphorylation of the EGFR/Jak2 chimera and Stat5, which correlated with the EGF dose dependence of cell proliferation. On the other hand, EGF did not induce tyrosine phosphorylation of other factors implicated in cytokine receptor signaling, including the IL-3 receptor beta subunit, Jak kinases, Stat proteins other than Stat5, Shc, Syp, and mitogen-activated protein kinases. These results suggest that the activation of Jak2 may be sufficient for transducing a growth signal in hematopoietic cells by activating the Stat5 pathway or previously unidentified signaling pathways. In addition, because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity, the present study, which shows EGF-dependent activation of the EGFR/Jak2 chimera, implies that Jak2 may also become activated by homodimerization.