Pilarczyk Götz, Nesnidal Ines, Gunkel Manuel, Bach Margund, Bestvater Felix, Hausmann Michael
Kirchhoff Institute for Physics, Im Neuenheimer Feld INF 227, D-69120 Heidelberg, Germany.
Bioquant-University of Heidelberg, Im Neuenheimer Feld INF 267, D-69120 Heidelberg, Germany.
Int J Mol Sci. 2017 Feb 9;18(2):362. doi: 10.3390/ijms18020362.
In cancer, vulnerable breast epithelium malignance tendency correlates with number and activation of ErbB receptor tyrosine kinases. In the presented work, we observe ErbB receptors activated by irradiation-induced DNA injury or neuregulin- 1 β application, or alternatively, attenuated by a therapeutic antibody using high resolution fluorescence localization microscopy. The gap junction turnover coinciding with ErbB receptor activation and co-transport is simultaneously recorded. DNA injury caused by 4 Gray of 6 MeV photon γ -irradiation or alternatively neuregulin- 1 β application mobilized ErbB receptors in a nucleograde fashion-a process attenuated by trastuzumab antibody application. This was accompanied by increased receptor density, indicating packing into transport units. Factors mobilizing ErbB receptors also mobilized plasma membrane resident gap junction channels. The time course of ErbB receptor activation and gap junction mobilization recapitulates the time course of non-homologous end-joining DNA repair. We explain our findings under terms of DNA injury-induced membrane receptor tyrosine kinase activation and retrograde trafficking. In addition, we interpret the phenomenon of retrograde co-trafficking of gap junction connexons stimulated by ErbB receptor activation.
在癌症中，易恶变的乳腺上皮细胞的恶变倾向与表皮生长因子受体（ErbB）受体酪氨酸激酶的数量和激活状态相关。在本研究中，我们使用高分辨率荧光定位显微镜观察到，ErbB受体可被辐射诱导的DNA损伤或应用神经调节蛋白-1β激活，或者被治疗性抗体减弱。同时记录了与ErbB受体激活和协同转运相一致的间隙连接更新情况。6兆电子伏特光子γ射线4格雷剂量的辐射或应用神经调节蛋白-1β所引起的DNA损伤，以核向运输的方式调动了ErbB受体，这一过程可被曲妥珠单抗抗体减弱。这伴随着受体密度增加，表明其被包装进运输单元。调动ErbB受体的因素也调动了质膜驻留的间隙连接通道。ErbB受体激活和间隙连接调动的时间进程概括了非同源末端连接DNA修复的时间进程。我们从DNA损伤诱导的膜受体酪氨酸激酶激活和逆向运输的角度解释了我们的发现。此外，我们还解释了由ErbB受体激活所刺激的间隙连接连接子逆向协同运输现象。
