Review
Membrane type 1-matrix metalloproteinase: Substrate diversity in pericellular proteolysis

https://doi.org/10.1016/j.semcdb.2007.06.008Get rights and content

Abstract

Enzymes in the matrix metalloproteinase (MMP) family have been linked to key events in developmental biology for almost 50 years. Biochemical, cellular and in vivo analyses have established that pericellular proteolysis contributes to numerous aspects of ontogeny including ovulation, fertilization, implantation, cellular migration, tissue remodeling and repair. Surface anchoring of proteinase activity provides spatial restrictions on substrate targeting. This review will utilize membrane type 1 MMP (MT1-MMP) as an example to highlight substrate diversity in pericellular proteolysis catalyzed by a membrane anchored MMP.

Introduction

Enzymes in the matrix metalloproteinase (MMP) family have been linked to key events in developmental biology since the first discovery of collagenolytic activity in amphibians undergoing metamorphosis by Gross and Lapiere in 1962 [1]. A plethora of subsequent biochemical, cellular and in vivo analyses have established that pericellular proteolysis contributes to numerous aspects of ontogeny, including ovulation, fertilization, implantation, cellular migration, tissue remodeling and repair. Stringent control of proteolysis is essential for maintenance of tissue integrity and homeostasis, and multiple mechanisms have evolved for both systemic and highly localized control of proteolytic activity [2], [3]. An effective mechanism for post-translational control of substrate processing is to anchor proteinases to the cell surface via a transmembrane domain, glycosyl-phosphatidyl inositol (GPI) anchor, or surface-localized proteinase receptor. Surface anchoring thereby provides spatial restrictions on substrate targeting and may afford protection from circulating proteinase inhibitors [4]. This review will utilize membrane type 1 (MT1)-MMP as an example to highlight substrate diversity in pericellular proteolysis. This captivating proteinase was originally discovered based on its ability to catalyze cell surface-associated processing of a soluble substrate, proMMP-2 [5], [6]. In recent years, however, a wealth of additional protein and polypeptide MT1-MMP substrates have been described, providing abundant examples to illustrate the diverse functional consequences of pericellular proteolytic processing of matrix, soluble, and cell surface-associated substrates.

MT1-MMP is comprised of seven domains, including a pre/propeptide (M1–R111), a catalytic domain (Y112–G285) containing the Zn2+-binding consensus region, a hinge or linker region (E286–I318), hemopexin domain (C319–C508), stalk region (P509–S538), transmembrane domain (A539–F562), and a cytoplasmic tail (R563–V582) [6], [7], [8], [9], [10] (Fig. 1). The enzyme is expressed as a zymogen (proMT1-MMP) containing a furin recognition motif (R108–R111) between the pro- and catalytic domains and is processed by proprotein convertases such as furin in the secretory pathway [11], [12]. MT1-MMP is thereby presented to the cell surface in active form and recent data suggest that zymogen activation may actually be a pre-requisite for plasma membrane trafficking of the proteinase [13], [14]. In addition to the catalytically competent 55–60 kDa active species, proteolytic processing generates a membrane anchored form (Fig. 1) lacking the catalytic domain [15], [16], [17], [18], [19]. This 44–45 kDa hemopexin domain-containing species may play a role in regulating activity of the mature enzyme [20], [21], [22], [23].

Section snippets

MT1-MMP as an interstitial collagenase

Shortly after discovery of the enzyme, early biochemical studies using active MT1-MMP retaining the hemopexin domain demonstrated the ability of MT1-MMP to process interstitial collagens I, II, and III in vitro, producing the 3/4 and 1/4 fragments characteristic of mammalian collagenases [24], [25]. Generation of mice deficient in MT1-MMP expression provided strong genetic evidence to support the in vitro data, demonstrating a key role for MT1-MMP as an interstitial collagenase during

Intracellular substrates

Although MT1-MMP is trafficked to the cell surface and processes predominantly extracellular substrates, summarized above, recent studies have identified an intracellular recycling pathway involving the tubulin cytoskeleton, resulting in accumulation of MT1-MMP in the centrosomal compartment [56], [57]. Processing of the centrosomal protein pericentrin can be catalyzed by MT1-MMP, leading to mitotic spindle aberrations. Ectopic expression of MT1-MMP in normal mammary epithelium led to enhanced

Autolysis

Expression of active MT1-MMP results in autolytic degradation and generation of a catalytically inactive species on the cell surface (Fig. 1) [15], [73], [74], [75]. Autolysis is the result of cleavage at G284–G285 in the linker region of MT1-MMP, followed by an additional cleavage at A255–I256 near the conserved methionine turn, rendering the resulting autolysis product catalytically inactive [19], [73]. Although lacking the catalytic domain, the 44 kDa transmembrane hemopexin domain-containing

Conclusion

In the relatively short time since its discovery, it has become well established that the transmembrane proteinase MT1-MMP is involved in the breakdown of extracellular matrix in normal physiological processes, such as tissue remodeling, embryonic development, and reproduction, as well as in disease processes, including arthritis and cancer metastasis. More recently, novel research tools and approaches have identified new substrates and molecular pathways as targets of MT1-MMP proteolysis,

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    M.V.B. is supported in part by a grant from the Illinois Department of Public Health. The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the Illinois Department of Public Health. Financial support was also provided by the 2006 Ovarian Cancer Research Foundation Program of Excellence award (M.V.B.) and the Katten Muchin Rosenman Travel Scholarship Award from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (M.V.B.). The authors also gratefully acknowledge financial support from National Cancer Institute Research Grant RO1 CA86984 (M.S.S.).

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