Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion
Introduction
Matrix metalloproteinases (MMPs) are a family of zinc-binding endopeptidases that collectively degrade most of the components of the extracellular matrix (ECM) [1], [2]. Extensive study in the last decade has revealed that MMPs are frequently overexpressed in most form of human tumor [3], [4], [5]. Based on their ECM-degrading activity, these MMPs are believed to contribute to the proliferation, invasion and metastasis of tumor cells by eliminating the surrounding ECM barrier. In addition, MMPs are required for tumor-induced angiogenesis. Thus, inhibition of the MMPs in tumor is expected to stabilize malignancy. Based on this assumption, different types of MMP inhibitors have been developed and indeed proved effective in animal models. However, recent clinical studies have failed to show a clear benefit from MMP inhibitors compared to conventional therapies [3], [6], [7]. Why aren't MMP inhibitors effective against human tumors? It is unlikely that MMPs do nothing. One possibility is their contribution differs depending on the stage of tumor development. Basically, MMP activity would be required for rapidly proliferating and invading tumors rather than the already established large tumors on which most of the clinical studies were carried out. Even in the animal models, MMP inhibitors are only effective in preventing an angiogenic switch and following tumor growth, having failed to reduce the size of late-stage tumors [8]. Thus, the protocols of clinical studies are now the subject of reevaluation taking into consideration the MMP inhibitor-sensitive stages and types of tumors.
More than 20 MMPs have been identified for mammals all with relatively conserved domains; a propeptide, a catalytic domain, and a hemopexin-like domain from the N-terminus, though there are some exceptions (Fig. 1) [3]. Still each MMP also has additional sequences that presumably contribute to their unique function. A C-terminal hydrophobic stretch in membrane-type 1 matrix metalloproteinase (MT1-MMP) is one example that anchors the enzyme to the plasma membrane and restricts its activity to the cell surface. The enzymes having such membrane-anchor signals are referred to as membrane-type MMPs (MT-MMPs) [9], [10]. Among the six MT-MMPs identified to date, MT1, MT2, MT3, and MT5 have a type I transmembrane domain, while MT4 and MT6-MMP are tethered to the plasma membrane by a GPI anchor [11], [12]. Since cells require remodeling of the pericellular ECM for proliferation, migration and morphogenesis, all of the MT-MMPs are presumably important for such cell functions [10], [13]. Among them, MT1-MMP has been additionally characterized as an enzyme required for tumor invasion.
Section snippets
MT1-MMP: basic information
MT1-MMP was the first membrane-type MMP identified and was characterized as a specific activator of proMMP-2 (pro-gelatinase A) at the cell surface [9]. As with all MMPs, the propeptide has to be removed for MT1-MMP to function proteolytically on the cell surface. MT1-MMP has a basic amino acid motif (RXKR) at the C-terminal end of the propeptide [9], [14], and cleavage occurs at this position by furin or related enzymes to generate the active form [15], [16], [17]. However, alternative
Expression of MT1-MMP in tumor
In the developing mouse embryo, MT1-MMP is mainly expressed in cells of mesenchymal origin including fibroblasts, muscular cells, and osteoblasts, and the expression decreases with maturation after birth [44], [45]. Expression can be re-induced, however, when the cells require remodeling ECM again. For example, the expression of MT1-MMP is induced in fibroblasts when tissue is damaged and continues throughout the healing process together with the expression of MMP-2 [46]. Since MT1-MMP has
Significance of membrane anchoring
Appearing as an active enzyme on the cell surface, MT1-MMP acts as part of the invasion machinery when it is expressed in migratory cells. Madin-Darby canine kidney (MDCK) cells derived from canine kidney epithelium develop a branched tubular structure when stimulated by hepatocyte growth factor (HGF) in 3-dimensional type I collagen gel. Surrounded by collagen, MDCK cells express MT1-MMP which was essential to the invasive and morphogenic responses of the cells to HGF [78]. Expression of
Conclusions
MT1-MMP is a potent ECM-degrading enzyme that acts as part of the invasion machinery when expressed in motile cells such as invasive tumor cells. To promote invasion, MT1-MMP has to be delivered to the migration front of cells as a complex with CD44, and shed CD44 to regulate CD44-dependent adhesion. Additionally it must form homo-oligomers to activate proMMP-2. On the other hand, down-regulation of MT1-MMP by internalization also looks important to keep the space for newly synthesized MT1-MMP
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