The cancer-associated meprin β variant G32R provides an additional activation site and promotes cancer cell invasion

• Published in: Journal of cell science Vol. 132; no. 11
• Main Authors: Schäffler, Henning, Li, Wenjia, Helm, Ole, Krüger, Sandra, Böger, Christine, Peters, Florian, Röcken, Christoph, Sebens, Susanne, Lucius, Ralph, Becker-Pauly, Christoph, Arnold, Philipp
• Format: Journal Article
• Language: English
• Published: England 01.06.2019
• Subjects: Shedding; ADAM17; Cell invasion; Protease; Meprin; Endometrium
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.220665

The extracellular metalloprotease meprin β is expressed as a homodimer and is primarily membrane bound. Meprin β can be released from the cell surface by its known sheddases ADAM10 and ADAM17. Activation of pro-meprin β at the cell surface prevents its shedding, thereby stabilizing its proteolytic activity at the plasma membrane. We show that a single amino acid exchange variant (G32R) of meprin β, identified in endometrium cancer, is more active against a peptide substrate and the IL-6 receptor than wild-type meprin β. We demonstrate that the change to an arginine residue at position 32 represents an additional activation site used by furin-like proteases in the Golgi, which consequently leads to reduced shedding by ADAM17. We investigated this meprin β G32R variant to assess cell proliferation, invasion through a collagen IV matrix and outgrowth from tumor spheroids. We found that increased meprin β G32R activity at the cell surface reduces cell proliferation, but increases cell invasion.