Abstract
ADAM (a disintegrin and metalloproteinase) 10 is a key member of the ADAM family of disintegrin and metalloproteinases which process membrane-associated proteins to soluble forms in a process known as 'shedding'. Among the major targets of ADAM10 are Notch, EphrinA2 and CD44. In many cell-based studies of shedding, the activity of ADAM10 appears to overlap with that of ADAM17, which has a similar active-site topology relative to the other proteolytically active ADAMs. The tissue inhibitors of metalloproteinases, TIMPs, have proved useful in the study of ADAM function, since TIMP-1 inhibits ADAM10, but not ADAM17; however, both enzymes are inhibited by TIMP-3. In the present study, we show that, in comparison with ADAM17 and the MMPs (matrix metalloproteinases), the N-terminal domains of TIMPs alone are insufficient for the inhibition of ADAM10. This knowledge could form the basis for the design of directed inhibitors against different metalloproteinases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM10 Protein
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ADAM17 Protein
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Cell Line, Tumor
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Enzyme Activation
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Humans
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Hyaluronan Receptors / metabolism
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mutation / genetics
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Protease Inhibitors / isolation & purification
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacology*
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RNA, Small Interfering / genetics
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Solubility
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Tissue Inhibitor of Metalloproteinase-1 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / isolation & purification*
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Tissue Inhibitor of Metalloproteinase-1 / metabolism*
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Tissue Inhibitor of Metalloproteinase-3 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / isolation & purification*
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Tissue Inhibitor of Metalloproteinase-3 / metabolism*
Substances
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Hyaluronan Receptors
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Membrane Proteins
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Protease Inhibitors
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RNA, Small Interfering
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Tissue Inhibitor of Metalloproteinase-1
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Tissue Inhibitor of Metalloproteinase-3
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human
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ADAM17 Protein
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ADAM17 protein, human