| First Author | Minder P | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 42 | Pages | 35201-35211 |
| PubMed ID | 22923609 | Mgi Jnum | J:316876 |
| Mgi Id | MGI:6842909 | Doi | 10.1074/jbc.M112.368910 |
| Citation | Minder P, et al. (2012) Meprinalpha transactivates the epidermal growth factor receptor (EGFR) via ligand shedding, thereby enhancing colorectal cancer cell proliferation and migration. J Biol Chem 287(42):35201-35211 |
| abstractText | Meprinalpha, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinalpha in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinalpha activity at primary tumor sites. A role for meprinalpha in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinalpha-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 meprinalpha is capable of shedding epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinalpha. The physiological effects of meprinalpha-mediated shedding of EGF and TGFalpha were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinalpha leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinalpha in the EGFR/MAPK signaling pathway indicates a role of meprinalpha in colorectal cancer progression. |
