Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 43, Pages 40650-40658Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M206203200
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The activation of latent proenzymes is an important mechanism for the regulation of localized proteolytic activity. Human meprin-alpha, an astacin-like zinc metalloprotease expressed in normal colon epithelial cells, is secreted as a zymogen into the intestinal lumen. Here, meprin is activated after propeptide cleavage by trypsin. In contrast, colorectal cancer cells secrete meprin-a in a non-polarized way, leading to accumulation and increased activity of meprin-alpha in the tumor stroma. We have analyzed the activation mechanism of promeprin-alpha in colorectal cancer using a co-culture model of the intestinal mucosa composed of colorectal adenocarcinoma cells (Caco-2) cultivated on filter supports and intestinal fibroblasts grown in the companion dish. We provide evidence that meprin-a is activated by plasmin and show that the presence of plasminogen in the basolateral compartment of the co-cultures is sufficient for promeprin-alpha activation. Analysis of the plasminogen-activating system in the co-cultures revealed that plasminogen activators produced and secreted by fibroblasts converted plasminogen to active plasmin, which in turn generated active meprin-alpha. This activation mechanism offers an explanation for the observed meprin-a activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer.
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