Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin.
N-cadherin is essential for excitatory synaptic contact in the hippocampus. Presenilin 1 (PS1) is located at sites of synaptic contact, forming a complex with N-cadherin and beta-catenin. Here, we report that human N-cadherin is cleaved by PS1/gamma-secretase in response to physiological concentration of glutamate (Glu) stimulation, yielding a fragment Ncad/CTF2. The expression of Ncad/CTF2 in neuronal cells led to its translocation to the nucleus, and caused a prominent enhancement of cytoplasmic and nuclear beta-catenin levels in a cell-cell contact dependent manner, via following mechanisms: 1, inhibition of beta-catenin phosphorylation; 2, transactivation of beta-catenin; and 3, inhibition of N-cadherin transcription, and finally enhanced beta-catenin nuclear signaling. Since the regulation of cellular beta-catenin level is essential for synaptic function, disruption in the cleavage of N-cadherin may be causally linked to the synaptic dysfunction associated with Alzheimer's disease (AD).
Uemura
Kengo
K
Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Kihara
Takeshi
T
Kuzuya
Akira
A
Okawa
Katsuya
K
Nishimoto
Takaaki
T
Bito
Haruhiko
H
Ninomiya
Haruaki
H
Sugimoto
Hachiro
H
Kinoshita
Ayae
A
Shimohama
Shun
S
D021581:Active Transport, Cell Nucleus; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D053764:Presenilin-1; D013569:Synapses / Q000378:metabolism; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism*
D015820:Cadherins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051176:beta Catenin