{"146041":{"#nid":"146041","#data":{"type":"news","title":"Cathepsin Cannibalism: Enzymes Attack One Another Instead of Harming Proteins","body":[{"value":"\u003Cp\u003EResearchers for the first time have shown that members of a family of enzymes known as cathepsins \u2013 which are implicated in many disease processes \u2013 may attack one another instead of the bodily proteins they normally degrade. Dubbed \u201ccathepsin cannibalism,\u201d the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.\u003C\/p\u003E\u003Cp\u003ECathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.\u003C\/p\u003E\u003Cp\u003EUsing a combination of modeling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme\u2019s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.\u003C\/p\u003E\u003Cp\u003E\u201cThese findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue \u2013 or fight against each other,\u201d said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. \u201cThere has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.\u201d\u003C\/p\u003E\u003Cp\u003EThe research was supported by the National Institutes of Health, the National Science Foundation and the Georgia Cancer Coalition. Details of the study were reported August 10 in the \u003Cem\u003EJournal of Biological Chemistry.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003EPlatt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S \u2013 two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.\u003C\/p\u003E\u003Cp\u003EWhen the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.\u003C\/p\u003E\u003Cp\u003EPlatt at first believed the experiment was flawed, and asked Barry \u2013 an undergraduate student in his lab who specializes in modeling \u2013 to examine what possible conditions could account for the experimental result. Barry\u2019s modeling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin \u2013 a protein essential in arteries and the cardiovascular system.\u003C\/p\u003E\u003Cp\u003EThat theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.\u003C\/p\u003E\u003Cp\u003E\u201cWe saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,\u201d said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. \u201cWe kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.\u201d\u003C\/p\u003E\u003Cp\u003EThe researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography \u2013 a sensitive technique developed in the Platt laboratory.\u003C\/p\u003E\u003Cp\u003EBeyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body\u2019s enzyme system \u2013 and may suggest why drugs designed to inhibit cathepsins haven\u2019t worked as intended.\u003C\/p\u003E\u003Cp\u003E\u201cThe effect of the cathepsins on one another complicates the system,\u201d said Platt. \u201cIf you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-target binding and side effects that were not anticipated.\u201d\u003C\/p\u003E\u003Cp\u003EPlatt\u2019s long-term research has focused on cathepsins, including the development of sensitive tools and assays to quantify their activity in cells and tissue, as well as potential diagnostic applications for breast, lung and cervical cancer. Cathepsins normally operate within cells to carry out housekeeping tasks such as breaking down proteins that are no longer needed.\u003C\/p\u003E\u003Cp\u003E\u201cThese enzymes are very powerful, but they have been overlooked because they are difficult to study,\u201d said Platt. \u201cWe are changing the way that people view them.\u201d\u003C\/p\u003E\u003Cp\u003EFor the future, Platt plans to study interactions of additional cathepsins \u2013 as many as three or four are released during certain disease processes \u2013 and to develop a comprehensive model of how these proteases interact while they degrade collagen and elastin. That model could be useful to the designers of future drugs.\u003C\/p\u003E\u003Cp\u003E\u201cAs we build toward a comprehensive model of how these enzymes work, we can begin to understand how they behave in the extracellular matrix around these cells,\u201d said Platt. \u201cThat will help us be smarter about how we go about treating diseases and designing new drugs.\u201d\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThe project described was supported by Award Number DP2OD007433 from the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Office of the Director, National Institutes of Health, or the National lnstitutes of Health. This material is also based on work supported by the National Science Foundation under the Science and Technology Center Emergent Behaviors of Integrated Cellular systems (EBICS) Grant No. CBET-0939511.\u003C\/em\u003E\u003Cbr \/\u003E\u003Cbr \/\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E75 Fifth Street, N.W, Suite 309\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia\u0026nbsp; 30308\u0026nbsp; USA\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cbr \/\u003E\u003Cstrong\u003EMedia Relations Assistance\u003C\/strong\u003E: John Toon (404-894-6986)(\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E).\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EResearchers for the first time have shown that members of a family of enzymes known as cathepsins \u2013 which are implicated in many disease processes \u2013 may attack one another instead of the proteins they normally degrade. Dubbed \u201ccathepsin cannibalism,\u201d the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Researchers for the first time have shown that enzymes that normally degrade proteins may attack each other instead."}],"uid":"27303","created_gmt":"2012-08-13 12:45:14","changed_gmt":"2016-10-08 03:12:40","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2012-08-13T00:00:00-04:00","iso_date":"2012-08-13T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"68625":{"id":"68625","type":"image","title":"Manu Platt, PhD - Assistant Professor, Department of Biomedical Engineering","body":null,"created":"1449177185","gmt_created":"2015-12-03 21:13:05","changed":"1475894597","gmt_changed":"2016-10-08 02:43:17","alt":"Manu Platt, PhD - Assistant Professor, Department of Biomedical Engineering","file":{"fid":"192620","name":"platt_2010.jpg","image_path":"\/sites\/default\/files\/images\/platt_2010_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/platt_2010_0.jpg","mime":"image\/jpeg","size":1277779,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/platt_2010_0.jpg?itok=EC2Vbd9_"}},"146021":{"id":"146021","type":"image","title":"Manu Platt - Cathepsin Cannibalism","body":null,"created":"1449178751","gmt_created":"2015-12-03 21:39:11","changed":"1475894779","gmt_changed":"2016-10-08 02:46:19","alt":"Manu Platt - Cathepsin Cannibalism","file":{"fid":"195075","name":"manu-platt.jpg","image_path":"\/sites\/default\/files\/images\/manu-platt_1.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/manu-platt_1.jpg","mime":"image\/jpeg","size":1025829,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/manu-platt_1.jpg?itok=xgN8-nrO"}}},"media_ids":["68625","146021"],"groups":[{"id":"1214","name":"News Room"}],"categories":[{"id":"140","name":"Cancer Research"},{"id":"146","name":"Life Sciences and Biology"}],"keywords":[{"id":"40431","name":"cathepsin"},{"id":"12515","name":"College of Engineering; Wallace H. Coulter Department of Biomedical Engineering; Emory; Children\u0027s Healthcare of Atlanta; pediatric nanomedicine;  Gang Bao"},{"id":"7735","name":"enzyme"},{"id":"40451","name":"inhibitor"},{"id":"10832","name":"Manu Platt"},{"id":"40441","name":"protease"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News \u0026amp; Publications Office\u003C\/p\u003E\u003Cp\u003E(404) 894-6986\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}