title: Meprinα transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration.
abstract: Meprinα, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinα in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinα activity at primary tumor sites. A role for meprinα in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinα-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinα is capable of shedding epidermal growth factor (EGF) and transforming growth factor-α (TGFα) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinα. The physiological effects of meprinα-mediated shedding of EGF and TGFα were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinα leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinα in the EGFR/MAPK signaling pathway indicates a role of meprinα in colorectal cancer progression.
authors.affiliation: Institute of Biochemistry and Molecular Medicine,University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Minder
authors.affiliation: Institute of Biochemistry and Molecular Medicine,University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland.
authors.forename: Elke
authors.initials: E
authors.lastname: Bayha
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Rudolf-Hoeber-Strasse 1, 24118 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: Institute of Biochemistry and Molecular Medicine,University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland. Electronic address: erwin.sterchi@ibmm.unibe.ch.
authors.forename: Erwin E
authors.initials: EE
authors.lastname: Sterchi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D020935:MAP Kinase Signaling System; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D008024:Ligands; D009363:Neoplasm Proteins; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D008666:Metalloendopeptidases; C053833:meprin A; C010531:actinonin