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.
Ahmad
Munirah
M
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Ishikawa.
Takino
Takahisa
T
Miyamori
Hisashi
H
Yoshizaki
Tomokazu
T
Furukawa
Mitsuru
M
Sato
Hiroshi
H
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