ReviewMembrane type 1-matrix metalloproteinase: Substrate diversity in pericellular proteolysis☆
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,
References (114)
ECM and cell surface proteolysis: regulating cellular ecology
Cell
(1997)- et al.
Cell surface binding and activation of gelatinase A induced by expression of membrane-type-1-matrix metalloproteinase (MT1-MMP)
FEBS Lett
(1996) Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion
Cancer Lett
(2003)- et al.
Membrane type-matrix metalloproteinases (MT-MMP)
Curr Top Dev Biol
(2003) - et al.
Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2
FEBS Lett
(1996) - et al.
Functional interplay between type I collagen and cell surface matrix metalloproteinase activity
J Biol Chem
(2001) - et al.
Mutational and structural analyses of the hinge region of membrane type 1-matrix metalloproteinase and enzyme processing
J Biol Chem
(2005) - et al.
Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme
J Biol Chem
(2002) - et al.
Type I collagen abrogates the clathrin-mediated internalization of membrane type 1 matrix metalloproteinase (MT1-MMP) via the MT1-MMP hemopexin domain
J Biol Chem
(2006) - et al.
Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation
J Biol Chem
(2000)
Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities
J Biol Chem
Collagen binding properties of the membrane type-1 matrix metalloproteinase (MT1-MMP) hemopexin C domain. The ectodomain of the 44-kDa autocatalytic product of MT1-MMP inhibits cell invasion by disrupting native type I collagen cleavage
J Biol Chem
Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules
J Biol Chem
MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover
Cell
Inhibition of type I collagen film degradation by tumour cells using a specific antibody to collagenase and the specific tissue inhibitor of metalloproteinases (TIMP)
Cell Biol Int Rep
Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases
Blood
Glycosylation broadens the substrate profile of membrane type 1 matrix metalloproteinase
J Biol Chem
Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix
Cell
A pericellular collagenase directs the 3-dimensional development of white adipose tissue [see comment]
Cell
Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression
J Biol Chem
Type I collagen stabilization of matrix metalloproteinase-2
Arch Biochem Biophys
Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells
J Biol Chem
Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium
J Biol Chem
Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII
J Biol Chem
Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins
Cell
Membrane type 1 matrix metalloprotease cleaves laminin-10 and promotes prostate cancer cell migration
Neoplasia (New York)
Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration
J Biol Chem
Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability
J Biol Chem
Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis
J Biol Chem
Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2
J Biol Chem
Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease
J Biol Chem
Cellular activation of proMMP-13 by MT1-MMP depends on the C-terminal domain of MMP-13
FEBS Lett
Characterization of the mechanisms by which gelatinase A, neutrophil collagenase, and membrane-type metalloproteinase MMP-14 recognize collagen I and enzymatically process the two alpha-chains
J Mol Biol
Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis
J Biol Chem
Mannose-binding lectin: the pluripotent molecule of the innate immune system
Immunol Today
Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency
J Biol Chem
Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1
J Biol Chem
Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo [see comment]
Blood
Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation
J Biol Chem
An alternative processing of integrin alpha (v) subunit in tumor cells by membrane type-1 matrix metalloproteinase
J Biol Chem
Processing of integrin alpha (v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase
J Biol Chem
Membrane type-1 matrix metalloproteinase (MT1-MMP) processing of pro-alphav integrin regulates cross-talk between alphavbeta3 and alpha2beta1 integrins in breast carcinoma cells
Exp Cell Res
Re-solving the cadherin–catenin–actin conundrum
J Biol Chem
Preoperative plasma soluble E-cadherin predicts metastases to lymph nodes and prognosis in patients undergoing radical cystectomy
J Urol
Low-density lipoprotein receptor-related protein (LRP)-mediated clearance of activated blood coagulation co-factors and proteases: clearance mechanism or regulation?[comment]
J Thromb & Haemostasis
Collagenolytic activity in amphibian tissues: a tissue culture assay
Proc Natl Acad Sci USA
Membrane associated matrix metalloproteinases in metastasis
Bioessays
Regulatory mechanisms for proteinase activity
A matrix metalloproteinase expressed on the surface of invasive tumour cells [see comment]
Nature
Matrix metalloproteinases: a tail of a frog that became a prince
Nat Rev Mol Cell Biol
Cited by (123)
Redox homeostasis in cardiac fibrosis: Focus on metal ion metabolism
2024, Redox BiologyThe role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis
2024, Biomaterials and BiosystemsCathepsin B: structure, function, tumorigenesis, and prognostic value in hepatocellular carcinoma
2022, Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma: Volume 3: Translational and Clinical OutcomesProteolytic processing of laminin and the role of cryptides in tumoral biology
2021, Proteolytic Signaling in Health and Disease
- ☆
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.).