Peptide EphB2/CTF2 generated by the γ-secretase processing of EphB2 receptor promotes tyrosine phosphorylation and cell surface localization of N-methyl-D-aspartate receptors

Abstract

Presenilin 1, a protein involved in the development of familial Alzheimer disease, is an important functional component of the γ-secretase complex that processes many cell surface receptors including the EphB2 tyrosine kinase receptors (Litterst, C., Georgakopoulos, A., Shioi, J., Ghersi, E., Wisniewski, T., Wang, R., Ludwig, A., and Robakis, N. K. (2007) J. Mol. Chem. 282, 16155-16163). Recent evidence reveals that cytosolic peptides produced by the combined metalloproteinase/γ-secretase processing of cell surface proteins function in signal transduction and protein phosphorylation. Here we show that peptide EphB2/CTF2 released to the cytosol by the γ-secretase processing of EphB2 receptor, has tyrosine kinase activity, and directly phosphorylates the N-methyl-D-aspartate, receptor (NMDAR) subunits in both cell lines and primary neuronal cultures. This phosphorylation occurs in the absence of Src kinases and is resistant to Src inhibitors revealing a novel pathway of NMDAR tyrosine phosphorylation independent of Src activity. EphB2/CTF2, but not a kinase-deficient mutant of EphB2/CTF2, promotes the cell surface expression of NMDAR. Because NMDAR plays central roles in synaptic plasticity and function, our results provide a potential link between the γ-secretase function of presenillin 1 and learning and memory. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.