From the School of Medicine, Tsinghua University, Beijing 100084, China and.
the Women's Cancer Research Center at the University of Pittsburgh Medical Center Hillman Cancer Center and.
J Biol Chem. 2018 Mar 9;293(10):3700-3709. doi: 10.1074/jbc.M117.789503. Epub 2018 Jan 12.
Breast cancer development and progression are influenced by insulin-like growth factor receptor 1 (IGF1R) and insulin receptor (InsR) signaling, which drive cancer phenotypes such as cell growth, proliferation, and migration. IGF1R and InsR form IGF1R/InsR hybrid receptors (HybRs) consisting of one molecule of IGF1R and one molecule of InsR. The specific signaling and functions of HybR are largely unknown, as HybR is activated by both IGF1 and insulin, and no cellular system expresses HybR in the absence of holo-IGF1R or holo-InsR. Here we studied the role of HybR by constructing inducible chimeric receptors and compared HybR signaling with that of holo-IGF1R and holo-InsR. We cloned chemically inducible chimeric IGF1R and InsR constructs consisting of the extracellular domains of the p75 nerve growth factor receptor fused to the intracellular β subunit of IGF1R or InsR and a dimerization domain. Dimerization with the drugs AP20187 or AP21967 allowed specific and independent activation of holo-IGF1R, holo-InsR, or HybR, resulting in activation of the PI3K pathway. Holo-IGF1R and HybR both promoted cell proliferation and glucose uptake, whereas holo-InsR only promoted glucose uptake, and only holo-IGF1R showed anti-apoptotic effects. We also found that the three receptors differentially regulated gene expression: holo-IGF1R and HybR up-regulated EGR3; holo-InsR specifically down-regulated JUN and BCL2L1; holo-InsR down-regulated but HybR up-regulated HK2; and HybR specifically up-regulated FHL2, ITGA6, and PCK2. Our findings suggest that, when expressed and activated in mammary epithelial cells, HybR acts in a manner similar to IGF1R and support further investigation of the role of HybR in breast cancer.
乳腺癌的发生和发展受到胰岛素样生长因子受体 1（IGF1R）和胰岛素受体（InsR）信号的影响，这些信号驱动着癌细胞的生长、增殖和迁移等表型。IGF1R 和 InsR 形成 IGF1R/InsR 杂合受体（HybR），由一个 IGF1R 分子和一个 InsR 分子组成。由于 HybR 被 IGF1 和胰岛素同时激活，而且在没有完整 IGF1R 或完整 InsR 的情况下，没有细胞系统表达 HybR，因此 HybR 的特定信号和功能在很大程度上是未知的。在这里，我们通过构建可诱导的嵌合受体来研究 HybR 的作用，并比较了 HybR 信号与完整 IGF1R 和完整 InsR 的信号。我们克隆了化学诱导的嵌合 IGF1R 和 InsR 构建体，这些构建体由 p75 神经生长因子受体的细胞外结构域与 IGF1R 或 InsR 的β亚基和二聚化结构域融合而成。与药物 AP20187 或 AP21967 的二聚化允许对完整的 IGF1R、完整的 InsR 或 HybR 进行特异性和独立的激活，从而激活 PI3K 通路。完整的 IGF1R 和 HybR 均促进细胞增殖和葡萄糖摄取，而完整的 InsR 仅促进葡萄糖摄取，只有完整的 IGF1R 显示出抗凋亡作用。我们还发现，这三种受体对基因表达的调节存在差异：完整的 IGF1R 和 HybR 上调 EGR3；完整的 InsR 特异性地下调 JUN 和 BCL2L1；完整的 InsR 下调但 HybR 上调 HK2；HybR 特异性地上调 FHL2、ITGA6 和 PCK2。我们的研究结果表明，当在乳腺上皮细胞中表达和激活时，HybR 的作用方式类似于 IGF1R，并支持进一步研究 HybR 在乳腺癌中的作用。
