PMID:11827968

Citation	Faisal Khan, KM, Laurie, GW, McCaffrey, TA and Falcone, DJ (2002) Exposure of cryptic domains in the alpha 1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression. J. Biol. Chem. 277:13778-86
Abstract	Degradation of the extracellular matrix leads to the release of fragments, which elicit biological responses distinct from intact molecules. We have reported that alpha1:Ser(2091)-Arg(2108), a peptide derived from the alpha1-chain of laminin-1, triggers protein kinase C-dependent activation of MAPK(erk1/2), leading to the up-regulation of macrophage urokinase type plasminogen activator and matrix metalloproteinase (MMP)-9 expression. Since intact laminin-1 failed to trigger these events, we hypothesized that alpha1:Ser(2091)-Arg(2108) is cryptic or assumes a conformation not recognized by macrophages. Here we demonstrate that elastase cleavage of laminin-1 generates fragments, which stimulate proteinase expression by RAW264.7 macrophages and peritoneal macrophages. In contrast, fragments generated by MMP-2, MMP-7, or plasmin had no effect on macrophage proteinase expression. Elastase-generated laminin-1 fragments were fractionated by heparin-Sepharose chromatography. Heparin-binding fragments stimulated macrophages' proteinase expression severalfold greater than nonbinding fragments. The heparin binding fragments reacted with antibodies directed against regions of the alpha1-chain including alpha1:Ser(2091)-Arg(2108) and the globular domain. A peptide from the first loop of the globular domain (alpha1:Ser(2179)-Ser(2198)) triggered the phosphorylation of MAPK(erk1/2) and stimulated the expression of macrophage urokinase type plasminogen activator and MMP-9. Moreover, a heparin-binding fraction isolated from an aortic aneurysm contained fragments of alpha1-chain and stimulated macrophages' proteinase expression. Based on these data, we conclude that cryptic domains in the COOH-terminal portion of the alpha1-chain of laminin are exposed by proteolysis and stimulate macrophages' proteinase expression.
Links	PubMed Online version:10.1074/jbc.M111290200
Keywords	Animals; Aortic Aneurysm/metabolism; Arginine/chemistry; Blotting, Western; Cattle; Cell Line; Chromatography; Fibrinolysin/metabolism; Humans; Laminin/chemistry; Laminin/metabolism; Macrophages/enzymology; Macrophages/metabolism; Matrix Metalloproteinase 2/metabolism; Matrix Metalloproteinase 7/metabolism; Matrix Metalloproteinase 9/biosynthesis; Mice; Pancreatic Elastase/metabolism; Peptides/chemistry; Phosphorylation; Protein Kinase C/metabolism; Protein Structure, Tertiary; Serine/chemistry; Time Factors; Urokinase-Type Plasminogen Activator/biosynthesis
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