Characterization of sequential N-cadherin cleavage by ADAM10 and PS1.
N-cadherin is essential for excitatory synaptic contact in the hippocampus. At the sites of synaptic contact, it forms a complex with Presenilin 1(PS1) and beta-catenin. N-cadherin is cleaved by ADAM10 in response to NMDA receptor stimulation, producing a membrane fragment Ncad/CTF1 in neurons. NMDA receptor stimulation also enhances PS1/gamma-secretase-mediated cleavage of N-cadherin. To characterize the regulatory mechanisms of the ADAM10 and PS1-mediated cleavages, we first identified the precise cleavage sites of N-cadherin by ADAM10 and PS1/gamma-secretase by producing cleavage-deficient N-cadherin mutants. Next, we found that ectodomain shedding of N-cadherin by ADAM10 is a primary regulatory step in response to calcium influx, and that it is required for the subsequent PS1/gamma-secretase-mediated epsilon-cleavage of N-cadherin, which is a constitutive process to yield a cytoplasmic fragment, Ncad/CTF2. Since N-cadherin is essential for the structure and function of synapses including the long-term potentiation, those proteolytic events of N-cadherin should affect the adhesive behavior of the synapses, thereby taking part in learning and memory.
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
Ninomiya
Haruaki
H
Sugimoto
Hachiro
H
Kinoshita
Ayae
A
Shimohama
Shun
S