ReviewMatrix metalloproteinases: they're not just for matrix anymore!
Introduction
The matrix metalloproteinases (MMPs) are a family of over 20 enzymes that cleave the various components of the extracellular matrix (ECM) ([1••]; Table 1). The MMPs are associated with a variety of normal and pathological conditions that involve matrix degradation and remodeling 2., 3., 4.. For example, MMPs are highly expressed in adult reproductive tissues undergoing dramatic reductions in tissue mass, including the endometrium during menstruation and the involuting breast, uterus and prostate [5]. MMPs contribute to connective tissue development, as demonstrated by the defects in bone and cartilage that occur in mice deficient for the MMPs membrane type 1 (MT1)-MMP and MMP-9 6., 7.. Several MMPs are expressed during wound healing, and mice deficient in MMP-3 and MMP-7 are defective in wound repair of the epidermis and trachea, respectively 8., 9.. The tissue destruction that occurs in diseases such as periodontitis, rheumatoid arthritis, macular degeneration and tumor cell invasion are mediated by members of the MMP family. Therefore, there has been substantial effort placed on generating synthetic inhibitors of MMPs for therapeutic use in these diseases [4].
It has become clear in recent years that the view that MMPs function as weapons for the mass destruction of the extracellular matrix is too simplistic. The ECM serves many roles in addition to its structural and barrier functions. For example, the basement membrane influences the growth and survival of epithelial cells, and the ECM serves as a reservoir for a variety of biologically active molecules [10]. Proteolysis of ECM components by MMPs can alter these functions, as well as result in the release of fragments with distinct biological activities [11]. In addition, a number of non-matrix substrates that potently influence cellular function have been identified. This review focuses on recent work identifying specific matrix and non-matrix MMP substrates and the biological consequence of their cleavage.
Section snippets
Matrix and non-matrix MMP substrates that alter cell growth
Cell proliferation is often regulated by the interaction of a mitogenic or growth-suppressive factor with its cell-surface receptor. There are several mechanisms by which MMP-mediated cleavage facilitates this interaction.
One mechanism is cleavage of matrix proteins associated with growth factors. Several growth factors, for example fibroblast growth factor (FGF) and transforming growth factor-β (TGF-β), have a strong affinity for matrix components, therefore proteolysis of specific matrix
Matrix and non-matrix MMP substrates that regulate apoptosis
The basement membrane contains signals for cell survival, and loss of these signals results in cell death through a specialized form of apoptosis referred to as anoikis (see review by Frisch and Screaton in this issue, pp 555–562) [24]. Degradation of the basement membrane and loss of cell survival signals have been proposed to underlie the effects of MMPs on apoptosis in the involuting mammary gland [25]. However, apoptosis may be affected by direct proteolysis of death-inducing signaling
Matrix and non-matrix MMP substrates in cell migration
Cell migration is a complex process that requires the coordinated regulation of cell–cell attachments, cell–matrix attachment and matrix remodeling. It seems intuitive that matrix proteolysis could directly modulate cell–matrix adhesion either by removal of sites of adhesion or by exposing a binding site. This can translate into an effect on cell migration, as MMP-2-dependent cleavage of laminin-5 induces keratinocyte migration [29], and MT1-MMP cleavage of laminin-5 allows migration of a
Matrix and non-matrix MMP substrates in cell–cell communication
MMPs play a role in releasing factors that act in a paracrine manner to influence the behavior of distinct cell types. Bergers et al. [37••] demonstrated that VEGF release by MMP-9 was important for angiogenesis in a mouse model of pancreatic islet tumors. Although the actual substrate has not been identified, MMP-9 in infiltrating immune cells was necessary to allow VEGF to interact with its receptor on endothelial cells. Similarly, MMP-9-dependent release of VEGF, which acts as a
Complex role of MMPs during tumor progression
The concept that proteolytic degradation of matrix barriers is critical for tumor cell invasion and metastasis to distant sites was articulated several decades ago by pioneers such as E Reich and L Liotta 42., 43.. This hypothesis has been substantiated by a large number of animal studies with natural and synthetic inhibitors of proteases of several classes, including MMPs 44., 45., 46.. As detailed above, what has become clear in recent years is the effect these proteases have on early stages
Conclusions
The recent literature cited above makes it clear that we need to expand upon the simplistic view that MMPs punch holes in basement membrane and extracellular matrix structures to a much more sophisticated vision of specific proteolytic events targeting both matrix and non-matrix substrates. What becomes complicated with this enhanced understanding is predicting the consequence of MMP cleavage in a complex biological system. As described above, MMP cleavage events are associated with both
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
•of special interest
••of outstanding interest
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