Cleavage of amyloid-beta precursor protein (APP) by membrane-type matrix metalloproteinases.
Amyloid-beta 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 beta peptide region known to produce a C-terminal fragment. The Swedish-type mutant of APP, which produces a high level of amyloid beta peptide, was more effectively cleaved by MT3-MMP than wild-type APP in both the presence and absence of Fe65; however, amyloid beta 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.
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Ishikawa.
Munirah
M
Ahmad
Takahisa
T
Takino
Hisashi
H
Miyamori
Tomokazu
T
Yoshizaki
Mitsuru
M
Furukawa
Hiroshi
H
Sato
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D006868:Hydrolysis; D020782:Matrix Metalloproteinases / Q000378:metabolism* / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D020782:Matrix Metalloproteinases