Riding the metalloproteinase roller coaster.
To many of us in the field, working on matrix metalloproteinases (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 "adisintegrin and metalloproteinase" (ADAMs), ADAMs with thrombospondin 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!
['Murphy|Gillian|G|']
D000818:Animals D001671:Biochemistry D020134:Catalytic Domain D016207:Cytokines D044127:Epigenesis, Genetic D005109:Extracellular Matrix D049673:History, 20th Century D006801:Humans D007249:Inflammation D007700:Kinetics D053511:Matrix Metalloproteinase 14 D045726:Metalloproteases D016296:Mutagenesis D010455:Peptides D011485:Protein Binding D015398:Signal Transduction D019715:Tissue Inhibitor of Metalloproteinase-1
matrix metalloproteinase (MMP) extracellular matrix proteinase ADAMTS tissue inhibitor of metalloproteinase (TIMP)