Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis.
As transmembrane, Ca2+-dependent cell-cell adhesion molecules, cadherins play a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins with a group of intracellular proteins, the catenins. In the present study, we have detected the expression of alpha-, beta-, and gamma-catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and alpha-catenin, with either beta- or gamma-catenin. In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and beta- and gamma- catenins but not alpha-catenin was associated with the activation of caspase-3 and prevented by the caspase inhibitor Z-VAD-fmk. The pattern of cadherin/catenin cleavage detected in apoptotic osteoblasts was reproduced in vitro by recombinant caspase-3. The presence of a 90-kDa extracellular domain fragment of N-cadherin in conditioned medium from apoptotic cells indicates that additional extracellular or membrane-associated proteases also are activated. Disruption of N-cadherin-mediated cell-cell adhesion with function-blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of beta-catenin. These findings provide compelling evidence that N-cadherin-mediated cell-cell adhesion promotes osteoblast survival and suggest that the underlying mechanism may involve activation of beta-catenin signaling.
Matrix Biochemistry Group, Rowett Research Institute, Aberdeen, Scotland.
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Hunter
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McGregor
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Robins
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism*; D051180:Desmoplakins; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; D051185:gamma Catenin
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C495292:JUP protein, human; D009842:Oligopeptides; D010446:Peptide Fragments; C083970:R-cadherin; D015534:Trans-Activators; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D051178:alpha Catenin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D051176:beta Catenin; D051185:gamma Catenin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1