At present, the human MMP family consists of 23 structurally related members (Table1). Historically, the MMPs were divided into subgroups of collagenases, gelati-nases, stromelysins, membrane-type MMPs, and other novel MMPs, on the basis of their specificity for ECM components. As the list of MMP substrates has grown and several MMPs can degrade a number of different ECM components, a sequential MMP numbering system has been adapted, and the MMPs are now grouped according to their structure. There are eight distinct structural classes of MMPs: five are secreted and three are membrane-type MMPs (Figure 1) (7).
MMPs are produced and secreted by a number of cell types, including fibrob-lasts, smooth muscle cells, and endothelial cells. They share several highly conserved domains, including an N-terminal propeptide domain that contains a "cystein switch" sequence that enfolds the zinc atom of the catalytic site to maintain the latency of pro-MMPs, a catalytic domain with a zinc binding site and a conserved methionine, and a C-terminal hemopexin-like domain linked to the catalytic domain by a proline rich hinge region. The catalytic domain contains a zinc binding motif HEXXHXXGXXH, in which the three histidine residues represent the three zinc ligands and the glutamic residue the active site. The hemopexin domain contains a single Cys-Cys bond and plays a role in substrate recognition (for example, it is required for collagenases to cleave triple helical interstitial collagens), interaction with TIMPs, and binding of the enzyme to ECM or cell surface (4-5).
The substrates of MMPs are primarily insoluble proteins of ECM, including interstitial and basement membrane collagens, glycoproteins such as laminin, fibronectin, vitronectin, tenascin and elastin as well as proteoglycans. However, more recent data demonstrate that certain MMPs can degrade proteins other than ECM proteins. Many cell membrane bound precursors of growth factors growth fac tor receptors (FGF receptor 1, HER2/neu, HER4) and cell adhesion molecules (CD 44, E-cadherin, integrin) have been reported to be MMP substrates. For example, MMP-11 can cleavage of insulin-like growth-factor-binding protein (IGF-BP) to release IGFs (8); MMP-12 can proteolytically process plasminogen to generate angiostatin, an inhibitor of angiogenesis (9); MMP-2 and MMP-9 can proteolytically activate and promote tumor invasion and angiogenesis (10); and finally, cleav age of the av integrin subunit precursor by MMP-14 enhances cancer cell migration (11). Although the significance of these observations is not entirely clear, they reflect the complex nature of MMPs in cancer progression.
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