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| Subject Categories: Signal Transduction | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 1242–1252, doi:10.1038/sj.emboj.7601031 Published online 2 March 2006 |
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| Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling |
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| Anastasios Georgakopoulos, Claudia Litterst, Enrico Ghersi, Lia Baki, ChiJie Xu, Geo Serban and Nikolaos K Robakis |
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Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, NYU, New York, NY, USA To whom correspondence should be addressed Nikolaos K Robakis, Departments of Psychiatry and Neuroscience, Mount Sinai School of Medicine, NYU, One Gustave Levy Pl. Box 1229, Annenberg Bldg., Room 22-44A, New York, NY 10029, USA. Tel.: +1 212 241 9380; Fax: +1 212 831 1947; E-mail: nikos.robakis@mssm.edu Received 26 May 2005; Revised 9 February 2006; Published online 2 March 2006. |
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| Abstract |
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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/ -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 -secretase. These data show that the PS1/-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, -secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and -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. |
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| Keywords: Alzheimer's disease, ephrinB, presenilin1, -secretase, Src kinase |
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