A secreted form of human ADAM9 has an alpha-secretase activity for APP.
ADAM9 (MDC9, meltrin gamma) is a member of the ADAM family of metalloproteases, which play important roles in cell-cell fusion, intracellular signaling, and other cellular functions. Here we cloned a novel form of human ADAM9, designated hADAM9s (s for short), which lacks the carboxyl-terminus. Human ADAM9s was found to be secreted from transfected COS cells. RT-PCR analysis demonstrated that the mRNA for hADAM9s is expressed in human brain, liver, heart, kidney, lung, and trachea. When hADAM9s was co-expressed in COS cells with APP and treated with phorbol ester, the APP was digested exclusively at the alpha-secretory site. These results suggest that hADAM9s has an alpha-secretase-like activity for APP. Non-amyloidgenic cleavage of APP may occur at the plasma membrane. Our new results support a new therapeutic strategy to decrease in the Abeta content by directly activating ADAM9 in the extracellular space.
Hotoda
Nika
N
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Koike
Hisashi
H
Sasagawa
Noboru
N
Ishiura
Shoichi
S
D051722:ADAM Proteins; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D019556:COS Cells; D003001:Cloning, Molecular; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution
D016564:Amyloid beta-Protein Precursor; D019483:Disintegrins; D008565:Membrane Proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D008666:Metalloendopeptidases