Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Anastasios Georgakopoulos, Claudia Litterst, Enrico Ghersi, Lia Baki, Chi Jie Xu, Geo Serban, Nikolaos K. Robakis

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

Bidirectional signaling triggered by interacting ephrinB receptors (EphB) and ephrinB ligands is crucial for development and function of the vascular and nervous systems. A signaling cascade triggered by this interaction involves activation of Src kinase and phosphorylation of ephrinB. The mechanism, however, by which EphB activates Src in the ephrinB-expressing cells is unknown. Here we show that EphB stimulates a metalloproteinase cleavage of ephrinB2, producing a carboxy-terminal fragment that is further processed by PS1/γ-secretase to produce intracellular peptide ephrinB2/CTF2. This peptide binds Src and inhibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr418. EphrinB2/CTF2-activated Src phosphorylates ephrinB2 and inhibits its processing by γ-secretase. These data show that the PS1/γ-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, γ-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and γ-secretase dominant-negative mutants inhibited the EphB-induced cleavage of ephrinB2 and Src autophosphorylation, raising the possibility that FAD mutants interfere with the functions of Src and ephrinB2 in the CNS.

Original languageEnglish
Pages (from-to)1242-1252
Number of pages11
JournalEMBO Journal
Volume25
Issue number6
DOIs
StatePublished - 22 Mar 2006
Externally publishedYes

Keywords

  • Alzheimer's disease
  • EphrinB
  • Presenilin1
  • Src kinase
  • γ-secretase

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