Presenilin-dependent Processing and Nuclear Function of γ-Protocadherins*
By I. Haas, M. Frank, Nathalie Véron, R. Kemler. Journal of Biological Chemistry, 2005
131 citations recorded by the source corpus.
The recently described protocadherin gene clusters encode cadherin-related proteins, which are highly expressed in the vertebrate nervous system. Here, we report biochemical studies addressing proteolytic processing of γ-protocadherins. These type-I transmembrane proteins are cleaved by a metalloproteinase in vivo, generating a soluble extracellular fragment and a carboxyl-terminal fragment associated with the cellular membrane. In addition, we show that the carboxyl-terminal fragment is a substrate for further cleavage mediated by presenilin. Consequently, accumulation of the fragment is found when γ-secretase is inactivated either by the specific presenilin-inhibitor L685,458 or in double mutant murine embryonic fibroblasts lacking both presenilin genes. The γ-secretase-generated carboxyl-terminal fragment is largely unstable but accumulates when proteasomal degradation is inhibited. Interestingly, the proteolytic fragment generated by γ-secretase can localize to the nucleus. This is the first report providing experimental evidence for a cell surface receptor signaling function of protocadherins regulated by proteolytic events.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a9370def8f0f80b20090fb7e80ac68dc8c01158d
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Citations in the corpus
- The genetics of Alzheimer disease: back to the future. (2010, background): “Some protocadherins have been proposed as g-secretase substrates (Haas et al., 2005), and it remains to be seen whether or not PCDH11X competes with APP for g-sec- retase.”