Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system
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...
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| Veröffentlicht in: | The Journal of biological chemistry 2002-10, Vol.277 (43), p.40650-40658 |
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| container_issue | 43 |
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| container_title | The Journal of biological chemistry |
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| creator | Rösmann, Sandra Hahn, Dagmar Lottaz, Daniel Kruse, Markus-N Stöcker, Walter Sterchi, Erwin E |
| description | 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-alpha 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-alpha 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-alpha activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer. |
| doi_str_mv | 10.1074/jbc.M206203200 |
| format | Article |
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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-alpha 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-alpha 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. 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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-alpha 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-alpha 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-alpha activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>Caco-2 Cells</subject><subject>Coculture Techniques</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>DNA Primers</subject><subject>Dogs</subject><subject>Fibroblasts - metabolism</subject><subject>Humans</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestines - cytology</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Models, Biological</subject><subject>Plasminogen - metabolism</subject><subject>Urokinase-Type Plasminogen Activator - metabolism</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1PwzAQhj2AaCmsjMgTW4o_42SsKr6kIhaYI8c5p6mSONgOUif-OqkaiVtuuOfe0z0I3VGypkSJx0Np1u-MpIxwRsgFWhLCaJIzmS3QdQgHMpXI6RVaUEaznAq5RL8bE5sfHRvXY2fxfux0jzsYfNMnuh32Gjc91thA22IztnH0gDtXQXuijWudBxP1NNO9AY-bgKNv6ho8VLg84rgHPLQ6dE3vapgi52t9jcMxROhu0KXVbYDbua_Q1_PT5_Y12X28vG03u8RwTmMCkithS8uBy7wSMlfSaJtzmzJaMiOIzTOjZaYyUxkpaGW4UIpKC8KmJZR8hR7OuYN33yOEWHRNOH2le3BjKBRLaSYUmcD1GTTeheDBFpOLTvtjQUlx0lxMmot_zdPC_Zw8lh1U__jsmP8BPbZ9VA</recordid><startdate>20021025</startdate><enddate>20021025</enddate><creator>Rösmann, Sandra</creator><creator>Hahn, Dagmar</creator><creator>Lottaz, Daniel</creator><creator>Kruse, Markus-N</creator><creator>Stöcker, Walter</creator><creator>Sterchi, Erwin E</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20021025</creationdate><title>Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system</title><author>Rösmann, Sandra ; Hahn, Dagmar ; Lottaz, Daniel ; Kruse, Markus-N ; Stöcker, Walter ; Sterchi, Erwin E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-e5374fbf3e359d45975caf93f621b2c40f98ca5878cdc541dc347715fe4f6beb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Base Sequence</topic><topic>Caco-2 Cells</topic><topic>Coculture Techniques</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>DNA Primers</topic><topic>Dogs</topic><topic>Fibroblasts - metabolism</topic><topic>Humans</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestines - cytology</topic><topic>Metalloendopeptidases - metabolism</topic><topic>Models, Biological</topic><topic>Plasminogen - metabolism</topic><topic>Urokinase-Type Plasminogen Activator - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rösmann, Sandra</creatorcontrib><creatorcontrib>Hahn, Dagmar</creatorcontrib><creatorcontrib>Lottaz, Daniel</creatorcontrib><creatorcontrib>Kruse, Markus-N</creatorcontrib><creatorcontrib>Stöcker, Walter</creatorcontrib><creatorcontrib>Sterchi, Erwin E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rösmann, Sandra</au><au>Hahn, Dagmar</au><au>Lottaz, Daniel</au><au>Kruse, Markus-N</au><au>Stöcker, Walter</au><au>Sterchi, Erwin E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-10-25</date><risdate>2002</risdate><volume>277</volume><issue>43</issue><spage>40650</spage><epage>40658</epage><pages>40650-40658</pages><issn>0021-9258</issn><abstract>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-alpha 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-alpha 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-alpha activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer.</abstract><cop>United States</cop><pmid>12189145</pmid><doi>10.1074/jbc.M206203200</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 2002-10, Vol.277 (43), p.40650-40658 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Base Sequence Caco-2 Cells Coculture Techniques Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology DNA Primers Dogs Fibroblasts - metabolism Humans Intestinal Mucosa - metabolism Intestines - cytology Metalloendopeptidases - metabolism Models, Biological Plasminogen - metabolism Urokinase-Type Plasminogen Activator - metabolism |
| title | Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system |
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