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: Petra Minder, Elke Bayha, Christoph Becker-Pauly, Erwin E Sterchi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 42 Pg. 35201-35211 (Oct 12 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22923609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Hydroxamic Acids
• Ligands
• Neoplasm Proteins
• Transforming Growth Factor alpha
• EGFR protein, human
• ErbB Receptors
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Metalloendopeptidases
• meprin A
• actinonin

Topics

• Anti-Bacterial Agents (pharmacology)
• Caco-2 Cells
• Cell Movement
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• ErbB Receptors (genetics, metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Ligands
• MAP Kinase Signaling System
• Metalloendopeptidases (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (drug effects, genetics)
• Transforming Growth Factor alpha (genetics, metabolism)