Nuclear localization of matrix metalloproteinases.
Matrix metalloproteinases (MMPs) were originally identified as matrixin proteases that act in the extracellular matrix. Recent works have uncovered nontraditional roles for MMPs in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized matrixins participate in many physiological and pathological cellular processes, in which they can act as both degradative and regulatory proteases. In this review, we discuss the transcriptional and translational control of matrixin expression, their regulation of intracellular sorting, and the structural basis of activation and inhibition. In particular, we highlight the emerging roles of various matrixin forms in diseases. The activity of matrix metalloproteinases is regulated at several levels, including enzyme activation, inhibition, complex formation and compartmentalization. Most MMPs are secreted and have their function in the extracellular environment. MMPs are also found inside cells, both in the nucleus, cytosol and organelles. The role of intracellular located MMPs is still poorly understood, although recent studies have unraveled some of their functions. The localization, activation and activity of MMPs are regulated by their interactions with other proteins, proteoglycan core proteins and / or their glycosaminoglycan chains, as well as other molecules. Complexes formed between MMPs and various molecules may also include interactions with noncatalytic sites. Such exosites are regions involved in substrate processing, localized outside the active site, and are potential binding sites of specific MMP inhibitors. Knowledge about regulation of MMP activity is essential for understanding various physiological processes and pathogenesis of diseases, as well as for the development of new MMP targeting drugs.
Department of Biomolecular Sciences, Section of Clinical Biochemistry, Unit of Cell Biology, University Carlo Bo of Urbino, Via O. Ubaldini 7, 61029 Urbino (PU), Italy. ferdinando.mannello@uniurb.it
Ferdinando
F
Mannello
Virginia
V
Medda
D021581:Active Transport, Cell Nucleus; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D003600:Cytosol / Q000201:enzymology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology; D005110:Extracellular Space / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats
D020782:Matrix Metalloproteinases