Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor
Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor
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DOI：
10.1038/sj.onc.1202678
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发表时间：
1999-06-03
期刊：
影响因子：
8
通讯作者：
Coffer, PJ
中科院分区：
文献类型：
--
作者：
Dijkers, PF;van Dijk, TB;Coffer, PJ
白细胞介素(IL)-3、IL-5和粒细胞巨噬细胞集落刺激因子(GM-CSF)调节靶细胞的增殖、分化和凋亡。这些细胞因子的受体由细胞因子特异性α亚基和共同的βc亚基组成，βc的酪氨酸磷酸化被认为在介导信号转导事件中发挥关键作用。我们研究了βc酪氨酸突变对多种信号转导途径激活的影响。蛋白激酶 B (PKB) 的激活需要 JAK2，并被显性负性磷脂酰肌醇 3-激酶 (PI3K) 抑制。 JAK2 的过度表达足以激活蛋白激酶 B (PKB) 和细胞外调节激酶 1 (ERK1)。研究发现酪氨酸 577 和 612 对 PKB 和 ERK1 的激活至关重要，但对 STAT 转录因子的激活无关。PKB 和 ERK 的激活都与增殖和凋亡的调节有关。我们生成了表达受体突变体的 GM-CSFR 稳定细胞系，以评估它们对这些过程的影响。 PKB 和 ERK 的激活均受到干扰，而 STAT 的激活不受影响。酪氨酸577和612对于最佳增殖是必需的，然而，这些酪氨酸残基的突变并不影响GM-CSF介导的细胞凋亡拯救。这些数据表明，虽然 βc 酪氨酸残基 577 和 612 的磷酸化对于最佳细胞增殖很重要，但可以通过明显独立于 PKB 或 ERK 激活的替代信号传导途径介导细胞凋亡的拯救。
Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate proliferation, differentiation and apoptosis of target cells. Receptors for these cytokines consist of a cytokine-specific alpha subunit and a common shared beta c subunit, Tyrosine phosphorylation of the beta c is thought to play a critical role in mediating signal transduction events. We have examined the effect of mutation of beta c tyrosines on the activation of multiple signal transduction pathways. Activation of protein kinase B (PKB) required JAK2 and was inhibited by dominant-negative phosphatidylinositol 3-kinase (PI3K). Overexpression of JAK2 was sufficient to activate both protein kinase B (PKB) and extracellular regulated kinase-1 (ERK1). Tyrosine 577 and 612 were found to be critical for the activation of PKB and ERK1, but not activation of STAT transcription factors, Activation of both PKB and ERK have been implicated in the regulation of proliferation and apoptosis. We generated GM-CSFR stable cell lines expressing receptor mutants to evaluate their effect on these processes. Activation of both PKB and ERK was perturbed, while STAT activation remained unaffected. Tyrosines 577 and 612 were necessary for optimal proliferation, however, mutation of these tyrosine residues did not affect GM-CSF mediated rescue from apoptosis. These data demonstrate that while phosphorylation of beta c tyrosine residues 577 and 612 are important for optimal cell proliferation, rescue from apoptosis can be mediated bg alternative signalling routes apparently independent of PKB or ERK activation.