Stöckmann Daniel, Spannbrucker Tim, Ale-Agha Niloofar, Jakobs Philipp, Goy Christine, Dyballa-Rukes Nadine, Hornstein Tamara, Kümper Alexander, Kraegeloh Annette, Haendeler Judith, Unfried Klaus
IUF-Leibniz-Institut für Umweltmedizinische Forschung, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
INM-Leibniz-Institut für Neue Materialien, Campus D2 2, 66123 Saarbrücken, Germany.
Nanomaterials (Basel). 2018 Apr 23;8(4):267. doi: 10.3390/nano8040267.
The epidermal growth factor receptor (EGFR) is an abundant membrane protein, which is essential for regulating many cellular processes including cell proliferation. In our earlier studies, we observed an activation of the EGFR and subsequent signaling events after the exposure of epithelial cells to carbon nanoparticles. In the current study, we describe molecular mechanisms that allow for discriminating carbon nanoparticle-specific from ligand-dependent receptor activation. Caveolin-1 is a key player that co-localizes with the EGFR upon receptor activation by carbon nanoparticles. This specific process mediated by nanoparticle-induced reactive oxygen species and the accumulation of ceramides in the plasma membrane is not triggered when cells are exposed to non-nano carbon particles or the physiological ligand EGF. The role of caveolae formation was demonstrated by the induction of higher order structures of caveolin-1 and by the inhibition of caveolae formation. Using an in vivo model with genetically modified mice lacking caveolin-1, it was possible to demonstrate that carbon nanoparticles in vivo trigger EGFR downstream signaling cascades via caveolin-1. The identified molecular mechanisms are, therefore, of toxicological relevance for inhaled nanoparticles. However, nanoparticles that are intentionally applied to humans might cause side effects depending on this phenomenon.
表皮生长因子受体（EGFR）是一种丰富的膜蛋白，对调节包括细胞增殖在内的许多细胞过程至关重要。在我们早期的研究中，我们观察到上皮细胞暴露于碳纳米颗粒后，EGFR会被激活以及随后的信号传导事件。在当前的研究中，我们描述了能够区分碳纳米颗粒特异性受体激活和配体依赖性受体激活的分子机制。小窝蛋白-1是一个关键因素，在碳纳米颗粒激活受体时，它与EGFR共定位。当细胞暴露于非纳米碳颗粒或生理配体表皮生长因子（EGF）时，由纳米颗粒诱导的活性氧和神经酰胺在质膜中的积累所介导的这一特定过程不会被触发。通过诱导小窝蛋白-1的高阶结构以及抑制小窝形成，证明了小窝形成的作用。使用缺乏小窝蛋白-1的基因改造小鼠的体内模型，有可能证明体内的碳纳米颗粒通过小窝蛋白-1触发EGFR下游信号级联反应。因此，所确定的分子机制在毒理学上与吸入的纳米颗粒相关。然而，故意应用于人类的纳米颗粒可能会根据这一现象产生副作用。
