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The Molecular Perspective: Matrix Metalloproteinase 2

The Scripps Research Institute, Department of Molecular Biology, La Jolla, California, USA

Correspondence: David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu WorldWideWeb: http://www.scripps.edu/pub/goodsell

Cancer cells metastasize when they gain the ability to migrate through the body. For cancers of the epithelium, basement membranes provide a major barrier blocking migration and metastasis. Basement membranes are thin, resilient sheets of tangled proteins, composed of a fishnet of ropey collagen fibers interlaced with laminin and proteoglycan. They are effective barriers that provide a structural base for the epithelia and endothelia, and separate them from the connective tissues. In particular, a basement membrane underlies the epithelial layer of skin cells, providing a layer of support and protection between our skin and the interior of the body.

Of course, barriers are seldom impenetrable in living things, and basement membranes are no exception. Specialized cells must be able to pass through basement membranes: lymphocytes must squeeze through as they search for invading organisms, and embryonic nerve cells and blood vessels creep through basement membranes during development. As these cells push through the tangle of membrane proteins, specialized proteinases, such as matrix metalloproteinase 2 (MMP2), clip collagen strands along the way. Cancer cells, being derived from normal human cells, also carry the genetic information needed to build these special collagen-cutting enzymes. When they overcome the regulatory barriers that block synthesis of these proteinases in most cells, cancer cells gain the ability to cross basement membranes and metastasize to distant regions of the body.

In a body built from 60,000 different kinds of proteins, proteinases are a tricky business at best. They must be carefully controlled or they can wreak havoc (think of the proteinases in rattlesnake toxin and the uncontrolled damage they cause). Many techniques are used to protect our proteins from stray proteinases. The sleek, streamlined digestive proteinases, promiscuous in their taste for protein targets, are built like hand grenades, with a pin that is pulled after they are ejected safely into the stomach or intestine. Proteinases such as thrombin have very short lifespans when activated and act only in a limited area before they perish. Proteinases such as renin recognize and cleave only a single protein target and thus are no danger to other proteins. The action of MMP2 is controlled by tethering. It is activated only after it is bound to the cell surface and is able to reach only those proteins that are within reach of a probing cellular pseudopodia.

MMP2 and other proteinases involved in cell migration are attractive targets for chemotherapy. Three approaches have been taken, with significant success in test systems. The first is to use the natural inhibitors of these proteinases, termed TIMPs (tissue inhibitors of matrix metalloproteinases). The second approach seeks to mimic the propeptide domain of MMP2. The enzyme is activated by removal of the 80-amino-acid propeptide, freeing the catalytic zinc ion for action. Peptide inhibitors that mimic this propeptide bind in its place, masking the zinc and returning the enzyme to its inactive state. Finally, synthetic compounds that mimic the substrate of the enzyme, acting as traditional active site inhibitors, are being designed and tested. Analogs of collagen, combined with potent zinc-binding groups, have shown promising results. Note, however, that this is necessarily a cytostatic approach to cancer chemotherapy, seeking not to destroy cancer cells, but instead to restore the normal regulation of migration, converting malignant cells into benign cells.

View larger version (151K): [in this window] [in a new window]   Figure 1. Matrix metalloproteinase 2. MMP2 is designed for careful surgery of basement membranes. It is composed of a single protein chain that folds into four separate domains. In this figure, carbon atoms are colored to distinguish each domain. The catalytic domain, with white carbon atoms, performs the cleavage reaction. In the active enzyme, shown at right, the zinc ion may just be seen deep within the active site cleft at the center of the domain, colored green and highlighted with an arrow. In the inactive enzyme, shown at left, the propeptide domain, with light green carbon atoms, covers the active site and blocks access to the zinc ion. In both forms, yellow carbon atoms identify the hemopexin domain, so named because of its similarity to the plasma protein hemopexin. It is thought to be involved in substrate recognition and interaction with TIMPs, the natural inhibitors of the enzyme. The fibronectin domains, with carbons in purple, mediate binding to denatured collagen. These illustrations were created using coordinates from file 1ck7 from the Protein Data Bank.

View larger version (139K): [in this window] [in a new window]   Figure 2. MMP2 in action. As cells force their way through basement membranes, a careful balance must be found. Just enough collagen must be clipped to allow passage of a cellular pseudopod, but enough structure must be left to allow the cell to gain purchase, attaching and pulling itself through. In the figure, a pseudopod is just breaking through a basement membrane. MMP2 molecules (in red, bound to receptors on the cell surface) are cutting collagen fibers (long, thin molecules in blue) that block the progress of the pseudopod. This allows integrins (the yellow, dimeric proteins on the cell surface) to adhere to laminin molecules (green, cross-shaped molecules) that are exposed on the raw edges of the opening.

	Additional Reading:

Top Additional Reading:

1. Morgunova E, Tuuttila A, Bergmann U et al. Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed. Science1999;284:1667–1670.[Abstract/Free Full Text]
2. Kohn EC, Liotta LA. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res1995;55:1856–1862.[Abstract/Free Full Text]
3. Shapiro SD. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr Opin Cell Biol1998;10:602–608.[Medline]
4. Basbaum CB, Werb Z. Focalized proteolysis: spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr Opin Cell Biol1996;8:731–738.[Medline]

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