PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells
PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells
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DOI：
10.1038/sj.onc.1208894
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发表时间：
2005-11-01
期刊：
影响因子：
8
通讯作者：
Haque, SJ
中科院分区：
文献类型：
--
作者：
Ghosh, MK;Sharma, P;Haque, SJ
多形性胶质母细胞瘤（GBM）细胞经常具有EGFR基因的扩增和/或功能获得性突变，导致穆尔多重信号传导途径的激活。阻断EGFR活化可抑制U87和D54 GBM细胞中AKT和Stat 3的活化，并诱导自发凋亡，这与Mcl-1稳态水平的降低相关。令人惊讶的是，抑制PI 3激酶（PI 3 K）活性，这反过来又抑制AKT活化，显著增加了U87和D54细胞中Stat 3的DNA结合活性。这不是由于酪氨酸磷酸化Stat 3水平的增加。相反，异位表达的组成性激活AKT显着降低Stat 3在293 T细胞中的DNA结合活性。有趣的是，通过激活AKT的calyculin A阻断GBM或293 T细胞中的蛋白磷酸酶2A活性，稳定了位于Stat 3的反式激活结构域（transactivation domain，STAT）中的穆尔个Ser/Thr残基的磷酸化，这反过来又完全消除了Stat 3的DNA结合活性。总的来说，这些结果表明，Stat 3和AKT都在U87和D54细胞中提供存活信号，并且通过PI 3 K-AKT途径的Stat 3-丝氨酸/苏氨酸磷酸化负控制Stat 3的DNA结合功能。
Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of mul tiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of mul tiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.