期刊
GLIA
卷 65, 期 7, 页码 1103-1118出版社
WILEY
DOI: 10.1002/glia.23147
关键词
gamma-secretase; ephrin-B; FAK; microglia; migration; podosomes; presenilin; Src
资金
- DFG [SFB645, KFO177, SFB704]
- ImmunoSensation [EXC 1023]
- Medical Research Council [MC_PC_17116] Funding Source: researchfish
- MRC [MC_PC_17116] Funding Source: UKRI
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. gamma-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 gamma-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 -secretase stimulates Src and focal adhesion kinase (FAK). Inhibition of -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 -secretase as well as ephrin-B2 as regulators of microglial migration.
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