Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein

MDC9, also known as meltrin gamma, is a membrane-anchored metalloprotease. MDC9 contains several distinct protein domains: a signal sequence followed by a prodomain and a domain showing sequence similarity to snake venom meta lloproteases, a disintegrin-like domain, a cysteine-rich region, an epiderm al-growth-factor-like repeat, a transmembrane domain and a cytoplasmic doma in. Here we demonstrate that MDC9 expressed in COS cells is cleaved between the prodomain and the metalloprotease domain. Further, when MDC9 was co-ex pressed in COS cells with amyloid precursor protein (APP695) and treated wi th phorbol ester, APP695 was digested exclusively at the alpha-secretory si te in MDC9-expressing cells. When an artificial alpha-secretory site mutant was also co-expressed with MDC9 and treated with phorbol ester, APP secret ed by alpha-secretase was not increased in conditional medium. Inhibition o f MDC9 by a hydroxamate-based metalloprotease inhibitor, SI-27, enhanced be ta-secretase cleavage. These results suggest that MDC9 has an alpha-secreta se-like activity and is activated by phorbol ester.