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

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/gamma-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 gamma-secretase. These data show that the PS1/gamma-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, gamma-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and gamma-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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cells, Cultured, Ephrin-B2, Fibroblasts, Genes, Dominant, Humans, Kidney, Membrane Proteins, Metalloproteases, Mice, Mice, Knockout, Oncogene Proteins, Phosphorylation, Phosphotransferases, Presenilin-1, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins pp60(c-src), Receptor, EphB2, Signal Transduction, src-Family Kinases
EMBO J.
Date: Mar. 22, 2006
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