title: Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1β, and Trastuzumab Application.
abstract: 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.
authors.affiliation: Kirchhoff Institute for Physics, Im Neuenheimer Feld INF 227, D-69120 Heidelberg, Germany. goetz.pilarczyk@kip.uni-heidelberg.de.
authors.forename: Götz
authors.initials: G
authors.lastname: Pilarczyk
authors.affiliation: Kirchhoff Institute for Physics, Im Neuenheimer Feld INF 227, D-69120 Heidelberg, Germany. ines.nesnidal@kip.uni-heidelberg.de.
authors.forename: Ines
authors.initials: I
authors.lastname: Nesnidal
authors.affiliation: Bioquant-University of Heidelberg, Im Neuenheimer Feld INF 267, D-69120 Heidelberg, Germany. manuel.gunkel@bioquant.uni-heidelberg.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gunkel
authors.affiliation: Kirchhoff Institute for Physics, Im Neuenheimer Feld INF 227, D-69120 Heidelberg, Germany. margund.bach@kip.uni-heidelberg.de.
authors.forename: Margund
authors.initials: M
authors.lastname: Bach
authors.affiliation: German Cancer Research Center, Im Neuenheimer Feld INF 280, D-69120 Heidelberg, Germany. f.bestvater@dkfz.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Bestvater
authors.affiliation: Kirchhoff Institute for Physics, Im Neuenheimer Feld INF 227, D-69120 Heidelberg, Germany. hausmann@kip.uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Hausmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D018613:Microscopy, Confocal; D020890:Neuregulin-1 / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C117467:neuregulin beta
keywords: DNA injury; ErbB receptor tyrosin kinase; breast cancer; gap junction; irradiation; neuregulin; retrograde trafficking; spectral precision distance microscopy; therapeutic antibody