ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3.
ADAM28, a member of a disintegrin and metalloproteinase (ADAM) family, has two isoforms, membrane-type form (ADAM28m) and secreted form (ADAM28s). Although ADAM28 is expressed and synthesized in a precursor form (proADAM28) by lymphocytes and some cancer cells, its activation mechanism and substrates remain unclear. Here, we report that proADAM28s of 65kDa is processed with active matrix metalloproteinase-7 (MMP-7) to 42- and 40-kDa forms which corresponds to active ADAM28s without propeptide. Processed ADAM28s digested insulin-like growth factor binding protein-3 (IGFBP-3) in both free and complex forms with IGF-I or IGF-II, and the digestion was prevented with EDTA, 1,10-phenanthroline, KB-R7785, tissue inhibitor of metalloproteinases-3 (TIMP-3), and TIMP-4. These data provide the first evidence that proADAM28s is activated by MMP-7 and ADAM28 digests IGFBP-3.
Mochizuki
Satsuki
S
Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
Shimoda
Masayuki
M
Shiomi
Takayuki
T
Fujii
Yutaka
Y
Okada
Yasunori
Y
D051722:ADAM Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology
D004792:Enzyme Precursors; D018972:Insulin-Like Growth Factor Binding Protein 3; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D007334:Insulin-Like Growth Factor I; D051722:ADAM Proteins; C410224:ADAM28 protein, human; D008666:Metalloendopeptidases; D020783:Matrix Metalloproteinase 7