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Matrix Metalloproteinases 2004
Matrix Metalloproteinases 2004
Matrix Metalloproteinases 2004
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extracellular matrix. Besides modulating tissue structure to facilitate remodeling, cell migration, etc. MMP activities can result in the generation of epitopes that act as cell effectors or the release of sequestered growth factors. Proteolysis of adhesion molecules, growth factors, cytokines, chemokines and receptors have all been documented (Sternlicht and Werb, 2001) and the potential effects on cell behaviour are multifarious. There are 24 human MMPs, and homologues can be identied in birds, African clawed toad (Xenopus laevis), zebrash (Danio rerio), fruit y (Drosophila melanogaster), sea urchin (Paracentrotus lividus), nematode (Caenorhabditis elegans) and Hydra (Hydra vulgaris), as well as in plants and algae. Because of their recognized role in disease the MMPs have long been considered as pharmacological targets, but their multiplicity, associated with their variable expression in different tissues and their apparently overlapping substrate specicities, has presented considerable challenges to those hoping to design suitable therapeutic inhibitors. As a consequence of their apparent redundancy, the majority of studies in which MMP genes have been ablated in mice have produced no overt or very subtle phenotypes, with the exception of MMP-14, which, when knocked out, gave defects in endochondral and intramembranous bone development. However, specic challenges to individual knockouts are yielding a clearer picture of novel tissue functions of the MMPs, at the level of both cell-cell and cell-matrix interactions (Sternlicht and Werb, 2001). The MMPs are zinc-dependent
The matrix metalloproteinases (MMPs) are one of the major families of proteinases that play key roles in the responses of cells to their microenvironment. Most notably the MMPs have the combined capacity to degrade all the components of the
Fibronectin-like repeats
Hemopexin-like domain
Soluble MMPs
Zn
CAT Pro
Zn
HP
Collagenases (MMP-1, MMP-8, MMP-13) Stromelysins (MMP-3, MMP-10) Metalloelastase (MMP-12) MMP-19, enamelysin (MMP-20) MMP-27 Stromelysin 3 (MMP-11) MMP-21 Epilysin (MMP-28)
CAT Pro
Zn
S HP
CAT Pro
S HP
S
jcs.biologists.org
MMP2
MMP2
MMP2
Zn
CAT
Membrane-associated MMPs
Membrane-type (MT-1) MMP, MT-2 MMP, MT-3 MMP, MT-5 MMP, MMP-5 (MMP-14, MMP-15, MMP-16 and MMP-24)
Pro
Zn
HP TM CD
Cell-cell interactions
Proteinase activation cascades S Proteinase inhibitor processing e.g. 1proteinase inhibitor Release of membrane growth factors e.g. TGF- S GPI Processing of chemokines Shedding of growth factor receptors e.g. TNFR-I and TNFR-II S CA Ig Shedding of adhesion molecules e.g. L-selectin, cadherins and CD44 ECM-bound or EC-milieu MMPs Endocytosis? Secretion/ activation Cell surface MMPs TIMP inhibition MMP
CAT Pro
S HP
Zn
CAT Pro TM
S HP
CA MMP (MMP-23)
Zn
CAT
Golgi apparatus
Cell-matrix interactions
Pro HP
Propeptide
CA
Zn
CAT
Hemopexin-like domain
Cysteine array
TM Transmembrane domain
CD
Gene transcription
Nucleus
GPI anchor
Ig
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endopeptidases of the superfamily Metzincins (MEROPS, the protease database). They have specic domain structures, minimally consisting of a propeptide and a catalytic domain (MMP-7 and MMP-26), commonly with the addition of a hemopexin-like, fourbladed propeller domain connected by a linker or hinge region (MMP-1, MMP3, MMP-8, MMP-11, MMP-12, MMP13, MMP-18, MMP-19, MMP-20, MMP-21, MMP-27 and MMP-28). Others have these features plus a bronectin-like domain of three type II repeats (MMP-2 and MMP-9) or a transmembrane region and a short cytoplasmic tail (MMP-14, MMP-15, MMP-16 and MMP-24), or a glycosylphosphatidyl anchor (MMP-17 and MMP-25). MMP-23 is exceptional in that it has unique cysteine-rich, proline-rich and IL-1 receptor type II like domains and might initially be anchored by an N-terminal transmembrane domain prior to propeptide processing. The propeptide of the MMPs contains a cysteine switch motif, PRCGXPD, in which the cysteine residue interacts with the catalytic zinc domain in order to maintain inactivity until the propeptide has been removed by proteolysis. The catalytic domains have the zinc-binding motif HEXGHXXGXXH, in which the three histidine residues ligate the zinc ion. Activation of the MMPs by propeptide removal is a critical feature of their regulation and, in the case of MMPs with the requisite RX(R/K)R motif (MMP-11, MMP-14, MMP-15, MMP16, MMP-21, MMP-23, MMP-24, MMP-25 and MMP-28), might be effected intracellularly by the action of trans-Golgi-localised proprotein convertases or, for the majority, by cleavage by plasmin, autolysis or the action of other MMPs at the cell surface. MMP activity may subsequently be regulated by the action of inhibitors, notably the tissue inhibitors of MMPs (TIMPs) TIMP-1, TIMP-2, TIMP-3 and TIMP-4 and the serum panproteinase inhibitor 2 macroglobulin (Baker et al., 2002) The TIMPs are sixloop disulphide-bonded proteins forming two domains. They interact via their Nterminal three disulphide-bonded loops with the active site cleft of the catalytic domain, although signicant interactions of the hemopexin-like domains of MMP2 and MMP-9 with the C-terminal domains of TIMPs appear to have
Recommended reading
Sternlicht, M. D. and Werb, Z. (2001). How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463-516. Baker, A. H., Edwards, D. R. and Murphy, G. (2002). Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J. Cell Sci. 115, 3719-3727. MEROPS: the Protease Database [http://merops. sanger.ac.uk].
Cell Science at a Glance on the Web Electronic copies of the poster insert are available in the online version of this article at jcs.biologists.org. The JPEG images can be downloaded for printing or used as slides.