Exposure of cryptic domains in the α1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression

Document Type

Journal Article

Publication Date



Journal of Biological Chemistry








Degradation of the extracellular matrix leads to the release of fragments, which elicit biological responses distinct from intact molecules. We have reported that α1: Ser2091-Arg2108 a peptide derived from the al-chain of laminin-1, triggers protein kinase C-dependent activation of MAPKerk1/2, 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 α1: Ser2091-Arg2108 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 α1-chain including α1: Ser2091-Arg2108 and the globular domain. A peptide from the first loop of the globular domain (α1: Ser2179-Ser2198) triggered the phosphorylation of MAPKerk1/2 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 α1-chain and stimulated macrophages' proteinase expression. Based on these data, we conclude that cryptic domains in the COOH-terminal portion of the α1-chain of laminin are exposed by proteolysis and stimulate macrophages' proteinase expression.