Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner.
Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner.
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DOI：
10.1091/mbc.e10-11-0923
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发表时间：
2011-06-01
影响因子：
3.3
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
He K;Jang SW;Joshi J;Yoo MH;Ye K
UNC5B在缺乏其同源配体网络蛋白的情况下诱导细胞凋亡，并作为肿瘤抑制因子。UNC5B是紫外线刺激下p53的直接转录靶点。我们发现Akt磷酸化PIKE-A，调控其与UNC5B的关联，并以p53依赖的方式抑制UNC5B引发的细胞凋亡。UNC5B作为肿瘤抑制因子，在缺乏其同源配体网蛋白的情况下诱导细胞凋亡。UNC5B是紫外线刺激下p53的直接转录靶点。我们发现Akt磷酸化PIKE-A，调控其与UNC5B的关联，并以p53依赖的方式抑制UNC5B引发的细胞凋亡。PIKE-A GTPase以鸟嘌呤核苷酸依赖的方式结合活性Akt并刺激其激酶活性。Akt反馈并磷酸化Ser-472上的PIKE-A，随后增强其对Akt激酶活性的刺激作用。与野生型细胞相比，PIKE−/−小鼠胚胎成纤维细胞（MEF）中Akt活性显著降低。pik - a直接与UNC5B相互作用，UNC5B受netrin-1激活的Akt调控。PIKE-A过表达通过下调p53来减少UNC5B的表达。敲除PIKE-A可以稳定p53，增加UNC5B，并加剧紫外线引发的细胞凋亡。Akt的缺失消除了PIKE-A对p53和UNC5B的抑制作用。因此，我们的研究结果支持Akt-磷酸化的PIKE-A抑制unc5b诱导的细胞凋亡，并通过p53失活降低其表达水平的观点。
UNC5B induces apoptosis in the absence of its cognate ligand netrins and acts as a tumor suppressor. UNC5B is a direct transcriptional target of p53 upon UV stimulation. Here we show that Akt phosphorylates PIKE-A and regulates its association with UNC5B and inhibits UNC5B-provoked apoptosis in a p53-dependent manner. UNC5B acts as a tumor suppressor, and it induces apoptosis in the absence of its cognate ligand netrins. UNC5B is a direct transcriptional target of p53 upon UV stimulation. Here we show that Akt phosphorylates PIKE-A and regulates its association with UNC5B and inhibits UNC5B-provoked apoptosis in a p53-dependent manner. PIKE-A GTPase binds active Akt and stimulates its kinase activity in a guanine-nucleotide–dependent way. Akt feeds back and phosphorylates PIKE-A on Ser-472 and subsequently enhances its stimulatory effect on Akt kinase activity. Akt activity is significantly reduced in PIKE −/− Mouse Embryonic Fibroblast (MEF) cells as compared to wild-type cells. PIKE-A directly interacts with UNC5B, which is regulated by netrin-1–activated Akt. Overexpression of PIKE-A diminishes UNC5B expression through down-regulation of p53. Knocking down PIKE-A stabilizes p53, increases UNC5B, and escalates UV-triggered apoptosis. Depletion of Akt abrogates PIKE-A's inhibitory effect on both p53 and UNC5B. Hence our findings support the notion that Akt-phosphorylated PIKE-A inhibits UNC5B-elicited apoptosis and reduces its expression level through inactivation of p53.