ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein
Prodomains of A disintegrin and metalloproteinase (ADAM) metallopeptidases can act as highly specific intra- and intermolecular inhibitors of ADAM catalytic activity. The mouse ADAM9 prodomain (proA9; amino acids 24–204), expressed and characterized from Escherichia coli, is a competitive inhibitor...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Society for Biochemistry and Molecular Biology
2013
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| Online Access: | http://hdl.handle.net/1721.1/76196 https://orcid.org/0000-0002-1801-5548 |
| _version_ | 1811090753246461952 |
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| author | Moss, Marcia L. Powell, Gary Miller, Miles Aaron Edwards, Lori Qi, Bin Qing-Xiang Amy, Sang De Strooper, Bart Tesseur, Ina Lichtenthaler, Stefan F. Taverna, Mara Zhong, Julia Li Dingwall, Colin Ferdous, Taheera Schlomann, Uwe Zhou, Pei Griffith, Linda G. Lauffenburger, Douglas A. Petrovich, Robert Bartsch, Jorg W. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Moss, Marcia L. Powell, Gary Miller, Miles Aaron Edwards, Lori Qi, Bin Qing-Xiang Amy, Sang De Strooper, Bart Tesseur, Ina Lichtenthaler, Stefan F. Taverna, Mara Zhong, Julia Li Dingwall, Colin Ferdous, Taheera Schlomann, Uwe Zhou, Pei Griffith, Linda G. Lauffenburger, Douglas A. Petrovich, Robert Bartsch, Jorg W. |
| author_sort | Moss, Marcia L. |
| collection | MIT |
| description | Prodomains of A disintegrin and metalloproteinase (ADAM) metallopeptidases can act as highly specific intra- and intermolecular inhibitors of ADAM catalytic activity. The mouse ADAM9 prodomain (proA9; amino acids 24–204), expressed and characterized from Escherichia coli, is a competitive inhibitor of human ADAM9 catalytic/disintegrin domain with an overall inhibition constant of 280 ± 34 nm and high specificity toward ADAM9. In SY5Y neuroblastoma cells overexpressing amyloid precursor protein, proA9 treatment reduces the amount of endogenous ADAM10 enzyme in the medium while increasing membrane-bound ADAM10, as shown both by Western and activity assays with selective fluorescent peptide substrates using proteolytic activity matrix analysis. An increase in membrane-bound ADAM10 generates higher levels of soluble amyloid precursor protein α in the medium, whereas soluble amyloid precursor protein β levels are decreased, demonstrating that inhibition of ADAM9 increases α-secretase activity on the cell membrane. Quantification of physiological ADAM10 substrates by a proteomic approach revealed that substrates, such as epidermal growth factor (EGF), HER2, osteoactivin, and CD40-ligand, are increased in the medium of BT474 breast tumor cells that were incubated with proA9, demonstrating that the regulation of ADAM10 by ADAM9 applies for many ADAM10 substrates. Taken together, our results demonstrate that ADAM10 activity is regulated by inhibition of ADAM9, and this regulation may be used to control shedding of amyloid precursor protein by enhancing α-secretase activity, a key regulatory step in the etiology of Alzheimer disease. |
| first_indexed | 2024-09-23T14:51:25Z |
| format | Article |
| id | mit-1721.1/76196 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:51:25Z |
| publishDate | 2013 |
| publisher | American Society for Biochemistry and Molecular Biology |
| record_format | dspace |
| spelling | mit-1721.1/761962022-10-01T22:56:30Z ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein Moss, Marcia L. Powell, Gary Miller, Miles Aaron Edwards, Lori Qi, Bin Qing-Xiang Amy, Sang De Strooper, Bart Tesseur, Ina Lichtenthaler, Stefan F. Taverna, Mara Zhong, Julia Li Dingwall, Colin Ferdous, Taheera Schlomann, Uwe Zhou, Pei Griffith, Linda G. Lauffenburger, Douglas A. Petrovich, Robert Bartsch, Jorg W. Massachusetts Institute of Technology. Department of Biological Engineering Miller, Miles Aaron Griffith, Linda G. Lauffenburger, Douglas A. Prodomains of A disintegrin and metalloproteinase (ADAM) metallopeptidases can act as highly specific intra- and intermolecular inhibitors of ADAM catalytic activity. The mouse ADAM9 prodomain (proA9; amino acids 24–204), expressed and characterized from Escherichia coli, is a competitive inhibitor of human ADAM9 catalytic/disintegrin domain with an overall inhibition constant of 280 ± 34 nm and high specificity toward ADAM9. In SY5Y neuroblastoma cells overexpressing amyloid precursor protein, proA9 treatment reduces the amount of endogenous ADAM10 enzyme in the medium while increasing membrane-bound ADAM10, as shown both by Western and activity assays with selective fluorescent peptide substrates using proteolytic activity matrix analysis. An increase in membrane-bound ADAM10 generates higher levels of soluble amyloid precursor protein α in the medium, whereas soluble amyloid precursor protein β levels are decreased, demonstrating that inhibition of ADAM9 increases α-secretase activity on the cell membrane. Quantification of physiological ADAM10 substrates by a proteomic approach revealed that substrates, such as epidermal growth factor (EGF), HER2, osteoactivin, and CD40-ligand, are increased in the medium of BT474 breast tumor cells that were incubated with proA9, demonstrating that the regulation of ADAM10 by ADAM9 applies for many ADAM10 substrates. Taken together, our results demonstrate that ADAM10 activity is regulated by inhibition of ADAM9, and this regulation may be used to control shedding of amyloid precursor protein by enhancing α-secretase activity, a key regulatory step in the etiology of Alzheimer disease. National Institutes of Health (U.S.) (Grant R01EB010246) National Institutes of Health (U.S.) (Grant R01GM081336) Heptagon Fund (London, England) Cancer Research UK Whitehead Foundation Duke University. School of Medicine (Bridge Funding Program) Germany. Bundesministerium für Bildung und Forschung China (National Fellowship from the Chinese Scholarship Council) Florida State University 2013-01-08T16:55:29Z 2013-01-08T16:55:29Z 2011-09 2011-09 Article http://purl.org/eprint/type/JournalArticle 0021-9258 1083-351X http://hdl.handle.net/1721.1/76196 Moss, M. L. et al. “ADAM9 Inhibition Increases Membrane Activity of ADAM10 and Controls α-Secretase Processing of Amyloid Precursor Protein.” Journal of Biological Chemistry 286.47 (2011): 40443–40451. Web. https://orcid.org/0000-0002-1801-5548 en_US http://dx.doi.org/10.1074/jbc.M111.280495 Journal of Biological Chemistry Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Society for Biochemistry and Molecular Biology American Society for Biochemistry and Molecular Biology |
| spellingShingle | Moss, Marcia L. Powell, Gary Miller, Miles Aaron Edwards, Lori Qi, Bin Qing-Xiang Amy, Sang De Strooper, Bart Tesseur, Ina Lichtenthaler, Stefan F. Taverna, Mara Zhong, Julia Li Dingwall, Colin Ferdous, Taheera Schlomann, Uwe Zhou, Pei Griffith, Linda G. Lauffenburger, Douglas A. Petrovich, Robert Bartsch, Jorg W. ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title | ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title_full | ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title_fullStr | ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title_full_unstemmed | ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title_short | ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein |
| title_sort | adam9 inhibition increases membrane activity of adam10 and controls α secretase processing of amyloid precursor protein |
| url | http://hdl.handle.net/1721.1/76196 https://orcid.org/0000-0002-1801-5548 |
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