The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase
The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase
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DOI：
10.1128/mcb.26.5.1754-1769.2006
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Sorensen, PHB
中科院分区：
文献类型：
--
作者：
Martin, MJ;Melnyk, N;Sorensen, PHB
通过胰岛素样生长因子 I 受体 (IGF-IR) 轴发出的信号对于许多主要作用的癌蛋白的转化至关重要。然而，IGF-IR 促进肿瘤发生的机制仍不清楚。为了检验这一点，我们比较了 IGF-IR 缺失的 R- 小鼠胚胎成纤维细胞和经过工程改造以重新表达 IGF-IR 的 R- 细胞（R+ 细胞）中致癌 ETV6-NTRK3 (EN) 嵌合酪氨酸激酶的转化特性。我们之前表明表达 EN 的 R- 细胞（R- EN 细胞）对转化有抵抗力，但在 R+ 细胞中这种转化会恢复。我们现在表明，虽然 R-EN 细胞具有完整的 Ras 细胞外信号调节激酶信号传导和细胞周期进程，但它们在磷脂酰肌醇-3-激酶 (PI3K)-Akt 激活方面存在缺陷，并在不依赖锚定的条件下经历脱离诱导的细胞凋亡 (失巢凋亡)。相反，表达 EN 的 R+ 细胞（R+ EN 细胞）抑制失巢凋亡并完全转化。 R-EN 细胞中对 IGF-IR 的需求可以通过激活的 Akt 或膜靶向形式的 EN 的异位表达来克服。此外，与 R-EN 细胞相比，R+ EN 细胞显示与 EN 相关的胰岛素受体底物 1 (IRS-1) 的膜定位显着增加。由于已知 EN 作为衔接蛋白结合 IRS-1，因此我们的研究结果表明 IGF-IR 可能具有将 EN/IRS-1 复合物定位到细胞膜的功能，进而促进 PI3K-Akt 激活和失巢凋亡抑制。
Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.