The PI3K/Akt signal hyperactivates Eya1 via the SUMOylation pathway.
The PI3K/Akt signal hyperactivates Eya1 via the SUMOylation pathway.
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Eya1 是器官特异性干细胞的保守关键调节因子。然而，异位 Eya1 活性会促进乳腺上皮细胞的转化。引发 Eya1 致癌活性的信号仍有待确定。在这里，我们证明 Akt1 激酶与 Eya1 发生物理相互作用，并使 Akt 激酶的保守共有位点磷酸化。 PI3K/Akt 信号传导增强 Eya1 转录活性，这很大程度上归因于磷酸化诱导的 Eya1 SUMOylation 减少。事实上，SUMO 化会抑制 Eya1 转录活性； PI3K/Akt 的药理和遗传激活可显着降低 Eya1 SUMOylation。野生型而非 Akt 磷酸化位点突变体 Eya1 变异体挽救了 EYA1 沉默乳腺癌细胞的细胞迁移表型，凸显了 Eya1 磷酸化的重要性。此外，敲除 EYA1 可使乳腺癌细胞对 PI3K/Akt1 抑制剂和放射治疗敏感。因此，PI3K/Akt 信号通路激活 Eya1。这些发现进一步表明，PI3K/Akt 信号传导对 SUMO 化的调节可能是肿瘤发生的一个重要方面。
Eya1 is a conserved critical regulator of organ-specific stem cells. Ectopic Eya1 activities, however, promote transformation of mammary epithelial cells. Signals that instigate Eya1 oncogenic activities remain to be determined. Here, we show that Akt1 kinase physically interacts with Eya1 and phosphorylates a conserved consensus site of the Akt kinase. PI3K/Akt signaling enhances Eya1 transcription activity, which largely attributes to the phosphorylation-induced reduction of Eya1 SUMOylation. Indeed, SUMOylation inhibits Eya1 transcription activity; and pharmacologic and genetic activation of PI3K/Akt robustly reduces Eya1 SUMOylation. Wild type but not Akt phosphorylation site mutant Eya1 variant rescues the cell migratory phenotype of EYA1-silenced breast cancer cells, highlighting the importance of Eya1 phosphorylation. Furthermore, knockdown EYA1 sensitizes breast cancer cells to the PI3K/Akt1 inhibitor and irradiation treatments. Thus, the PI3K/Akt signal pathway activates Eya1. These findings further suggest that regulation of SUMOylation by PI3K/Akt signaling is likely an important aspect of tumorigenesis.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
64.8
作者：
Li, X;Oghi, KA;Rosenfeld, MG
通讯作者：
Rosenfeld, MG
DOI：
10.1073/pnas.95.21.12608
发表时间：
1998-10-13
影响因子：
11.1
作者：
Ford, HL;Kabingu, EN;Pardee, AB
通讯作者：
Pardee, AB
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
2.6
作者：
Machon, O;Backman, M;Krauss, S
通讯作者：
Krauss, S