title: Intramembranous processing by γ-secretase regulates reverse signaling of ephrin-B2 in migration of microglia.
abstract: 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.
authors.affiliation: Department of Neurology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Nadja
authors.identifier: 0000-0002-0218-2157
authors.initials: N
authors.lastname: Kemmerling
authors.affiliation: Department of Neurology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wunderlich
authors.affiliation: Department of Neurology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Theil
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Linnartz-Gerlach
authors.affiliation: Institute of Complex Systems, ICS-7 Biomechanics, Forschungszentrum Jülich GmbH, Jülich, 52425, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Hersch
authors.affiliation: Institute of Complex Systems, ICS-7 Biomechanics, Forschungszentrum Jülich GmbH, Jülich, 52425, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hoffmann
authors.affiliation: Department of Neurology, University of Bonn, Bonn, 53127, Germany.|German Center for Neurodegenerative Diseases, Bonn, 53127, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: KULeuven Centre for Human Genetics, Leuven, 3000, Belgium.|Centre for Brain and Disease, VIB (Flanders Institute for Biotechnology), Leuven, 3000, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: de Strooper
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Harald
authors.identifier: 0000-0002-5071-5202
authors.initials: H
authors.lastname: Neumann
authors.affiliation: Department of Neurology, University of Bonn, Bonn, 53127, Germany.
authors.forename: Jochen
authors.identifier: 0000-0002-4678-2912
authors.initials: J
authors.lastname: Walter
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism*; D004622:Embryo, Mammalian; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology* / Q000502:physiology*; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D036225:Receptor, EphB1 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000502:physiology
chemical_list: D036388:Ephrin-B2; D053764:Presenilin-1; D036225:Receptor, EphB1; D051417:Focal Adhesion Kinase 1; D016392:Proto-Oncogene Proteins pp60(c-src); C496051:Ptk2 protein, mouse; D053829:Amyloid Precursor Protein Secretases
keywords: FAK; Src; ephrin-B; microglia; migration; podosomes; presenilin; γ-secretase