Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

• Published in: The Journal of biological chemistry 2012-10, Vol.287 (42), p.35201-35211
• Main Authors: Minder, Petra, Bayha, Elke, Becker-Pauly, Christoph, Sterchi, Erwin E.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Caco-2 Cells; Cell Movement; Cell Proliferation; Colorectal Cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Ectodomain Shedding; Epidermal Growth Factor Receptor (EGFR); ErbB Receptors - genetics; ErbB Receptors - metabolism; ERK; Humans; Hydroxamic Acids - pharmacology; Ligands; MAP Kinase Signaling System; Meprin; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Metalloprotease; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphorylation - drug effects; Phosphorylation - genetics; Signal Transduction; Transforming Growth Factor alpha - genetics; Transforming Growth Factor alpha - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.368910

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. Background: EGFR signaling pathway activation is a crucial step in colorectal cancer tumor progression. Results: Meprinα sheds the epidermal growth factor ligands EGF and TGFα. Phosphorylation of EGFR and ERK1/2 is increased and cell proliferation and migration is enhanced after stimulation with meprinα. Conclusion: Meprinα transactivates the EGFR by proteolytic processing of TGFα and EGF. Significance: Meprinα may be a therapeutic target in colorectal cancer treatment.