© 2006 The Japanese Biochemical Society.
Regular Paper |
Cleavage of Amyloid-ß Precursor Protein (APP) by Membrane-Type Matrix Metalloproteinases
1 Department of Molecular Virology and Oncology, Cancer Research Institute; and 2 Department of Otolaryngology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934
* To whom correspondence should be addressed. Tel: +81-76-265-2748, Fax: +81-76-234-4504, E-mail: vhsato{at}kenroku.kanazawa-u.ac.jp
Amyloid-ß precursor protein (APP) was identified on expression cloning from a human placenta cDNA library as a gene product that modulates the activity of membrane-type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with APP in HEK293T cells induced cleavage and shedding of the APP ectodomain when co-expressed with APP adaptor protein Fe65. Among the MT-MMPs tested, MT3-MMP and MT5-MMP also caused efficient APP shedding. The recombinant APP protein was cleaved by MT3-MMP in vitro at the A463-M464, N579-M580, H622-S623, and H685-Q686 peptide bonds, which included a cleavage site within the amyloid ß peptide region known to produce a C-terminal fragment. The Swedish-type mutant of APP, which produces a high level of amyloid ß peptide, was more effectively cleaved by MT3-MMP than wild-type APP in both the presence and absence of Fe65; however, amyloid ß peptide production was not affected by MT3-MMP expression. Expression of MT3-MMP enhanced Fe65-dependent transactivation by APP fused to the Gal4 DNA–binding and transactivation domains. These results suggest that MT1-MMP, MT3-MMP and MT5-MMP should play an important role in the regulation of APP functions in tissues including the central nervous system.