Presenilin1/gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk binding protein
FASEB j.. 2011-07-11; 25(10): 3594-3604
DOI: 10.1096/fj.11-187856
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Georgakopoulos A(1), Xu J, Xu C, Mauger G, Barthet G, Robakis NK.
Author information:
(1)Center for Molecular Biology and Genetics of Neurodegeneration, Department of
Psychiatry, Mt. Sinai School of Medicine, New York University, 1 Gustave L. Levy
Pl., Box 1229, New York, NY 10029, USA.
Reverse signaling through the ephrinB ligands is important for several
morphogenetic events, such as axon guidance, neuronal plasticity, spine
maturation, and synaptogenesis. Signaling is initiated by binding of EphB
receptors to ephrinB ligands, stimulating their tyrosine phosphorylation via an
unclear mechanism. Here we show that this mechanism involves presenilin1
(PS1)/γ-secretase regulation of phosphoprotein associated with
glycosphingolipid-enriched microdomains/Csk binding protein (PAG/Cbp), an adaptor
protein that controls the activity of Src kinases. Using immunoprecipitation and
Western blot of mouse primary neuronal and human embryonic kidney (HEK293) cell
extracts overexpressing PAG/Cbp, we show that EphB2 induces tyrosine
dephosphorylation of PAG/Cbp in a γ-secretase-dependent manner. In these cells,
PAG/Cbp dephosphorylation is promoted by the PS1/γ-secretase-produced fragment of
ephrinB2 cleavage (ephrinB2/CTF2), which forms complexes with PAG/Cbp when
introduced exogenously. EphB2-induced tyrosine phosphorylation of ephrinB2
depends on PAG/Cbp because EphB2 cannot increase ephrinB2 phosphorylation in
cells treated with anti-PAG siRNA or in PAG/Cbp-knockout (KO) cells. Furthermore,
in contrast to WT PS1, familial Alzheimer disease (FAD) PS1 mutants expressed in
PS1-KO mouse embryonic fibroblasts inhibited both the EphB2-induced
dephosphorylation of PAG/Cbp and the phosphorylation of ephrinB2. PS1 FAD
mutations may thus inhibit the function of ephrinB in the brain, promoting
neurodegeneration in Alzheimer disease.