Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase
Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase
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DOI：
10.1073/pnas.94.8.3627
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发表时间：
1997-04-15
影响因子：
11.1
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Ahmed, NN;Grimes, HL;Tsichlis, PN
白介素 2 (IL-2) 受体 (IL-2R) 由三个亚基组成。其中，高亲和力 IL-2 结合需要 IL-2R α，而 IL-2R β 和 IL-2R gamma(c) 则需要转导 IL-2 生成的信号。通过 BAF/3 细胞中 IL-2R beta 的 S 区（氨基酸 267-322）转导的信号激活磷脂酰肌醇 3-激酶（PI3-激酶）并诱导 Bcl-2 和 c-myc 的表达。通过 Bcl-2 的诱导，IL-2 抑制细胞凋亡，并通过 Bcl-2 和 c-myc 的结合刺激细胞周期的进展。在这里，我们证明 Akt 原癌基因编码的蛋白激酶被 IL-2 激活。 IL-2 对 Akt 的激活取决于通过 IL-2R beta 的 S 区转导的 PI3 激酶信号，并且与 Akt 易位至细胞膜有关。在表达 IL-2R beta[A0]Delta S 的 BAF/3 细胞中催化活性 Akt 突变体的表达促进 Bcl-2 和 c-myc 的表达，抑制 IL-3 剥夺或十字孢菌素诱导的细胞凋亡，并刺激细胞周期进程。相同的突变体还刺激 2780a 中的细胞周期进程，2780a 是一种 IL-2 依赖性 T 细胞系，在 IL-2 剥夺后发生 G(1) 停滞而不是凋亡。 IL-2 通过 PI3 激酶激活 Akt 以及催化活性 Akt 拯救 PI3 激酶介导的抗凋亡和增殖 IL-2 信号表明这些信号是由 Akt 转导的。
The interleukin-2 (IL-2) receptor (IL-2R) is composed of three subunits. Of these, IL-2R alpha is required for high-affinity IL-2 binding, while IL-2R beta and IL-2R gamma(c) are required for the transduction of IL-2-generated signals. Signals transduced via the S region of the IL-2R beta (amino acids 267-322) in BAF/3 cells activate the phosphatidylinositol 3-kinase (PI3-kinase) and induce the expression of Bcl-2 and c-myc. Through the induction of Bcl-2, IL-2 inhibits apoptosis and through the combination of Bcl-2 and c-myc it stimulates progression through the cell cycle. Here we show that the protein kinase encoded by the Akt proto-oncogene is activated by IL-2. Akt activation by IL-2 depends on PI3-kinase signals transduced via the S region of the IL-2R beta and is linked to the translocation of Akt to the cell membrane. Expression of catalytically active Akt mutants in BAF/3 cells expressing IL-2R beta[A0]Delta S promotes the expression of Bcl-2 and c-myc, inhibits apoptosis induced by IL-3 deprivation or staurosporine, and stimulates cell cycle progression. The same mutants also stimulate cell cycle progression in 2780a, an IL-2-dependent T cell line that undergoes G(1) arrest rather than apoptosis after IL-2 deprivation. The activation of Akt by IL-2 via the PI3-kinase and the rescue of the PI3-kinase-mediated antiapoptotic and proliferative IL-2 signals by catalytically active Akt indicate that these signals are transduced by Akt.