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

Meprin alpha, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprin alpha in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprin alpha activity at primary tumor sites. A role for meprin alpha in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprin alpha-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 meprin alpha is capable of shedding epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprin alpha. The physiological effects of meprin alpha-mediated shedding of EGF and TGF alpha were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprin alpha leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprin alpha in the EGFR/MAPK signaling pathway indicates a role of meprin alpha in colorectal cancer progression.