Review
Matrix metalloproteinases: they're not just for matrix anymore!

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Abstract

The matrix metalloproteinases (MMPs) have been viewed as bulldozers, destroying the extracellular matrix to permit normal remodeling and contribute to pathological tissue destruction and tumor cell invasion. More recently, the identification of specific matrix and non-matrix substrates for MMPs and the elucidation of the biological consequence of cleavage indicates that perhaps MMPs should be viewed more as pruning shears, playing sophisticated roles in modulating normal cellular behavior, cell–cell communication and tumor progression.

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

References (76)

  • D.C Von Bredow et al.

    Cleavage of β4 integrin by matrilysin

    Exp Cell Res

    (1997)
  • T.H Vu et al.

    MMP-9/Gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes

    Cell

    (1998)
  • L Ossowski et al.

    Antibodies to plasminogen activator inhibit human tumor metastasis

    Cell

    (1983)
  • M.D Sternlicht et al.

    The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis

    Cell

    (1999)
  • L.M Coussens et al.

    MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis

    Cell

    (2000)
  • Z Dong et al.

    Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma

    Cell

    (1997)
  • B.C Patterson et al.

    Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/ type IV collagenase (MMP-9)

    J Biol Chem

    (1997)
  • H.I Park et al.

    Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor

    J Biol Chem

    (2000)
  • Z Liu et al.

    The serpin α1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo

    Cell

    (2000)
  • A.M Belkin et al.

    Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion

    J Biol Chem

    (2001)
  • D Pei

    Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP

    J Biol Chem

    (1999)
  • Y Wang et al.

    Catalytic activities and substrate specificity of the human membrane type 4 matrix metalloproteinase catalytic domain

    J Biol Chem

    (1999)
  • W.R English et al.

    Catalytic activities of membrane-type 6 matrix metalloproteinase (MMP25)

    FEBS Lett

    (2001)
  • D Pei

    CA-MMP: a matrix metalloproteinase with a novel cysteine array, but without the classic cysteine switch

    FEBS Lett

    (1999)
  • J.O Stracke et al.

    Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme

    J Biol Chem

    (2000)
  • J.O Stracke et al.

    Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)

    FEBS Lett

    (2000)
  • J.F Woessner et al.

    Matrix Metalloproteinases and TIMPs

    (2000)
  • T.H Vu et al.

    Matrix metalloproteinases: effectors of development and normal physiology

    Genes Dev

    (2000)
  • R.A Greenwald et al.

    Inhibition of Matrix Metalloproteinases: Therapeutic Applications

    (1999)
  • D.L Hulboy et al.

    Matrix metalloproteinases as mediators of reproductive function

    Mol Hum Reprod

    (1997)
  • Z Zhou et al.

    Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I

    Proc Natl Acad Sci USA

    (2000)
  • K.M Bullard et al.

    Impaired wound contraction in stromelysin-1-deficient mice

    Ann Surg

    (1999)
  • S.E Dunsmore et al.

    Matrilysin expression and function in airway epithelium

    J Clin Invest

    (1998)
  • K Imai et al.

    Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta 1 release

    Biochem J

    (1997)
  • J.L Fowlkes et al.

    Proteolysis of insulin-like growth factor binding protein-3 during rat pregnancy: a role for matrix metalloproteinases

    Endocrinology

    (1994)
  • K.M Thrailkill et al.

    Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation

    Endocrinology

    (1995)
  • D.C Martin et al.

    Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1

    J Cell Biol

    (1999)
  • Q Yu et al.

    Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-( and promotes tumor invasion and angiogenesis

    Genes Dev

    (2000)
  • Cited by (0)

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