Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.
We have investigated the effects of ligation of the fibronectin receptor (FnR) on gene expression in rabbit synovial fibroblasts. Monoclonal antibodies to the FnR that block initial adhesion of fibroblasts to fibronectin induced the expression of genes encoding the secreted extracellular matrix-degrading metalloproteinases collagenase and stromelysin. That induction was a direct consequence of interaction with the FnR was shown by the accumulation of mRNA for stromelysin and collagenase. Monoclonal antibodies to several other membrane glycoprotein receptors had no effect on metalloproteinase gene expression. Less than 2 h of treatment of the fibroblasts with anti-FnR in solution was sufficient to trigger the change in gene expression, and induction was blocked by dexamethasone. Unlike other inducers of metalloproteinase expression, including phorbol diesters and growth factors, addition of the anti-FnR in solution to cells adherent to serum-derived adhesion proteins or collagen produced no detectable change in cell shape or actin microfilament organization. Inductive effects were potentiated by cross-linking of the ligand. Fab fragments of anti-FnR were ineffective unless cross-linked or immobilized on the substrate. Adhesion of fibroblasts to native fibronectin did not induce metallo-proteinases. However, adhesion to covalently immobilized peptides containing the arg-gly-asp sequence that were derived from fibronectin, varying in size from hexapeptides up to 120 kD, induced collagenase and stromelysin gene expression. This suggests that degradation products of fibronectin are the natural inductive ligands for the FnR. These data demonstrate that signals leading to changes in gene expression are transduced by the FnR, a member of the integrin family of extracellular matrix receptors. The signaling of changes in gene expression by the FnR is distinct from signaling involving cell shape and actin cytoarchitecture. At least two distinct signals are generated: the binding of fibronectin-derived fragments and adhesion-blocking antibodies to the FnR triggers events different from those triggered by binding of the native fibronectin ligand. Because the genes regulated by this integrin are for enzymes that degrade the extracellular matrix, these results suggest that information transduced by the binding of various ligands to integrins may orchestrate the expression of genes regulating cell behavior in the extracellular environment.
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Laboratory of Radiobiology and Environmental Health, University of California, San Francisco 94143.
Tremble
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PM
Behrendtsen
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Crowley
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Damsky
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CH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D003012:Microbial Collagenase / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D017469:Receptors, Fibronectin; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D005353:Fibronectins; D017469:Receptors, Fibronectin; D011971:Receptors, Immunologic; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase