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

The extracellular metalloprotease meprin ß is expressed as a homodimer and is primarily membrane bound. Meprin ß can be released from the cell surface by its known sheddases ADAM10 and ADAM17. Activation of pro-meprin ß 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 ß, identified in endometrium cancer, is more active against a peptide substrate and the IL-6 receptor than wild-type meprin ß. 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 ß G32R variant to assess cell proliferation, invasion through a collagen IV matrix and outgrowth from tumor spheroids. We found that increased meprin ß G32R activity at the cell surface reduces cell proliferation, but increases cell invasion.