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.

TOCI: Schematic showing the γ-secretase dependent regulation of microglial migration. Upon binding of the EphB1 receptor to the extracellular domain (A), ephrin-B2 undergoes ectodomain shedding (B). The resulting C-terminal fragment (CTF) is subsequently cleaved by γ-secretase within its transmembrane domain (C) thereby liberating the ephrin-B2 intracellular domain (ICD). The ICD can promote phosphorylation of Src and FAK possibly through binding to Src (D). The kinase activation of Src and FAK might regulate podosomal turn-over (E) and microglial migration (F).

• γ-Secretase cleaves ephrin-B2 in microglia. The ephrin-B2 intracellular domain regulates phosphorylation of Src/FAK, podosomal dynamics, and microglial motility. γ-Secretase regulates reverse signaling of ephrin-B2 in microglia.

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