Kemmerling, N; Wunderlich, P; Theil, S; Linnartz-Gerlach, B; Hersch, N; Hoffmann, B; Heneka, MT; ... Walter, J; + view all Kemmerling, N; Wunderlich, P; Theil, S; Linnartz-Gerlach, B; Hersch, N; Hoffmann, B; Heneka, MT; de Strooper, B; Neumann, H; Walter, J; - view fewer (2017) Intramembranous processing by γ-secretase regulates reverse signaling of ephrin-B2 in migration of microglia. Glia , 65 (7) pp. 1103-1118. 10.1002/glia.23147.

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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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