Intramembranous processing by γ-secretase regulates reverse signaling of ephrin-B2 in migration of microglia

Kemmerling, Nadja; Walter, Jochen; Heneka, Michael T.; Wunderlich, Patrick; Neumann, Harald; Hersch, Nils; Theil, Sandra; Linnartz-Gerlach, Bettina; de Strooper, Bart; Hoffmann, Bernd

doi:10.1002/glia.23147

Journal Article

FZJ-2017-03118

Intramembranous processing by γ-secretase regulates reverse signaling of ephrin-B2 in migration of microglia

Kemmerling, N. ; Wunderlich, P. ; Theil, S. ; Linnartz-Gerlach, B. ; Hersch, N.FZJ* ; Hoffmann, B.FZJ* ; Heneka, M. T. ; de Strooper, B. ; Neumann, H. ; Walter, J. (Corresponding author)

2017
Wiley-Liss Bognor Regis [u.a.]

Glia 65(7), 1103–1118 (2017) [10.1002/glia.23147]

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Please use a persistent id in citations: http://hdl.handle.net/2128/15965 doi:10.1002/glia.23147

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.

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