Presenilin-dependent processing and nuclear function of gamma-protocadherins.
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 gamma-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 gamma-secretase is inactivated either by the specific presenilin-inhibitor L685,458 or in double mutant murine embryonic fibroblasts lacking both presenilin genes. The gamma-secretase-generated carboxyl-terminal fragment is largely unstable but accumulates when proteasomal degradation is inhibited. Interestingly, the proteolytic fragment generated by gamma-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.
Haas
Ingrid G
IG
Max-Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany. haasi@immunbio.mpg.de
Frank
Marcus
M
Véron
Nathalie
N
Kemler
Rolf
R
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts; D006801:Humans; D007668:Kidney; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D000070585:Cadherin Related Proteins; D015820:Cadherins; D002219:Carbamates; D004151:Dipeptides; C464785:Gamma-protocadherins; C410009:L 685458; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D020782:Matrix Metalloproteinases