Characterization of sequential N-cadherin cleavage by ADAM10 and PS1

Neurosci Lett. 2006 Jul 24;402(3):278-83. doi: 10.1016/j.neulet.2006.04.018. Epub 2006 May 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Cadherins / biosynthesis
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Endopeptidases / metabolism
  • Endopeptidases / physiology*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology


  • Cadherins
  • Receptors, N-Methyl-D-Aspartate
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • Calcium