[en] The Eph-ephrin system plays pivotal roles in cell adhesion and migration. The receptor-like functions of the ephrin ligands allow the regulation of intracellular processes via reverse signaling. γ-Secretase mediated processing of ephrin-B has previously been linked to activation of Src, a kinase crucial for focal adhesion and podosome phosphorylation. Here, we analyzed the role of γ-secretase in the stimulation of reverse ephrin-B2 signaling in the migration of mouse embryonic stem cell derived microglia. The proteolytic generation of the ephrin-B2 intracellular domain (ICD) by γ-secretase stimulates Src and focal adhesion kinase (FAK). Inhibition of γ-secretase decreased the phosphorylation of Src and FAK, and reduced cell motility. These effects were associated with enlargement of the podosomal surface. Interestingly, expression of ephrin-B2 ICD could rescue these effects, indicating that this proteolytic fragment mediates the activation of Src and FAK, and thereby regulates podosomal dynamics in microglial cells. Together, these results identify γ-secretase as well as ephrin-B2 as regulators of microglial migration.
Disciplines :
Neurology
Author, co-author :
Kemmerling, Nadja ; Department of Neurology, University of Bonn, Bonn, 53127, Germany
Wunderlich, Patrick; Department of Neurology, University of Bonn, Bonn, 53127, Germany
Theil, Sandra; Department of Neurology, University of Bonn, Bonn, 53127, Germany
Linnartz-Gerlach, Bettina; Institute of Reconstructive Neurobiology, University of Bonn, Bonn, 53127, Germany
Hersch, Nils; Institute of Complex Systems, ICS-7 Biomechanics, Forschungszentrum Jülich GmbH, Jülich, 52425, Germany
Hoffmann, Bernd; Institute of Complex Systems, ICS-7 Biomechanics, Forschungszentrum Jülich GmbH, Jülich, 52425, Germany
HENEKA, Michael ; Department of Neurology, University of Bonn, Bonn, 53127, Germany ; German Center for Neurodegenerative Diseases, Bonn, 53127, Germany
de Strooper, Bart; KULeuven Centre for Human Genetics, Leuven, 3000, Belgium ; Centre for Brain and Disease, VIB (Flanders Institute for Biotechnology), Leuven, 3000, Belgium
Neumann, Harald ; Institute of Reconstructive Neurobiology, University of Bonn, Bonn, 53127, Germany
Walter, Jochen ; Department of Neurology, University of Bonn, Bonn, 53127, Germany
External co-authors :
yes
Language :
English
Title :
Intramembranous processing by γ-secretase regulates reverse signaling of ephrin-B2 in migration of microglia.
We are grateful to Dr. C. Beutner for the generation of ESdM, Dr. D. Wachten for allowing us to work with the Nikon Eclipse Ti fluorescence microscope, H. Hamzeh for his great technical support regarding TIRF microscopy, Dr. C. Glebov for the technical support with live imaging, A. Viera-Saecker for providing primary microglia, A. -L. Scheithauer for her general support, and Dr. O. Brüstle for the lentiviral expression plasmid. This project was supported by the DFG (SFB645, KFO177, and SFB704). H. Neumann, B. Linnartz-Gerlach, and M. T. Heneka are members of the DFG-funded excellence cluster “ImmunoSensation” (EXC 1023).
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