Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion.
Gamma-protocadherins (Pcdh gamma) are type I transmembrane proteins, which are most notably expressed in the nervous system. They are enriched at synapses and involved in synapse formation, specification, and maintenance. In this study, we show that Pcdh gamma C3 and Pcdh gamma B4 are specifically cleaved within their ectodomains by the disintegrin and metalloprotease ADAM10. Analysis of ADAM10-deficient fibroblasts and embryos, inhibitor studies, as well as RNA interference-mediated down-regulation demonstrated that ADAM10 is not only responsible for the constitutive but also for the regulated shedding of these proteins in fibroblasts and in neuronal cells. In contrast to N-cadherin shedding, which was activated by N-methyl-D-aspartic acid receptor activation in neuronal cells, Pcdh gamma shedding was induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate stimulation, suggesting differential regulation mechanisms of cadherin-mediated functions at synapses. Cell aggregation assays in the presence or absence of metalloprotease inhibitors strongly suggest that the ectodomain shedding events modulate the cell adhesion role of Pcdh gamma. The identification of ADAM10 as the protease responsible for constitutive and regulated Pcdh gamma shedding may therefore provide new insight into the regulation of Pcdh gamma functions.
Reiss
Karina
K
Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany.
Maretzky
Thorsten
T
Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany.
Haas
Ingrid G
IG
Max Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany.
Schulte
Marc
M
Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany.
Ludwig
Andreas
A
Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany.
Frank
Marcus
M
Max Planck Institute of Immunobiology, Department of Molecular Embryology, Stuebeweg 51, Freiburg D-79108, Germany.
Saftig
Paul
P
Biochemical Institute, Christian-Albrecht-University Kiel, D-24098 Kiel, Germany. Electronic address: psaftig@biochem.uni-kiel.de.
D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D015153:Blotting, Western; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology; D013569:Synapses
D000070585:Cadherin Related Proteins; D015820:Cadherins; D008565:Membrane Proteins; C081682:PCDHGC3 protein, human; C504472:Pcdhgc3 protein, mouse; D018698:Glutamic Acid; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse