title: Riding the metalloproteinase roller coaster.
abstract: To many of us in the field, working onmatrixmetalloproteinases (MMPs) has felt like riding a roller coaster, traveling through times of both excitement and despair. I was fortunate to join the ride when it was a mere carousel of three activities thought to target the proteins that comprise the extracellular matrix (ECM). New technologies brought the thrills of discovery as we uncovered specific proteinase genes and defined specialized activities in different cellular processes. The MMPs and the sister families of "adisintegrinandmetalloproteinase" (ADAMs), ADAMs withthrombospondin domains (ADAM-TS), and Astacins are now recognized as key signaling "scissors" that drive rapid changes in a plethora of cellular pathways. My many excellent colleagues and collaborators and I were enthused to contribute to the early development of the field and continue to be amazed at its growth and sophistication. In contrast, the hype and failure of early inhibitor discovery have dogged our standing with the pharmaceutical industry and grant-giving bodies. However, the true believers have kept going, and knowledge of particular functions of MMPs and their contributions to disease progression has progressed. Recognition of the strategic importance of proteinase function should inspire more work harnessing new technologies such as imaging, proteomics, and gene editing to generate a more precise understanding of individual situations. New approaches to inhibitor design and assessment are possible, and the consequent ability to precisely abrogate specific MMP activity could contribute to the fight against a number of pathologies with unmet needs. What a ride it could be!
authors.affiliation: From the Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom gm290@cam.ac.uk.
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000266:history; D020134:Catalytic Domain; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D005109:Extracellular Matrix / Q000378:metabolism; D049673:History, 20th Century; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism*; D016296:Mutagenesis; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D010455:Peptides; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D045726:Metalloproteases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: ADAMTS; extracellular matrix; matrix metalloproteinase (MMP); proteinase; tissue inhibitor of metalloproteinase (TIMP)