Báo cáo khoa học: Localizing matrix metalloproteinase activities in the pericellular environment doc

MINIREVIEW Localizing matrix metalloproteinase activities in the pericellular environment Gillian Murphy1 and Hideaki Nagase2 Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK Department of Matrix Biology, The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, UK Keywords CD44; collagen; extracellular matrix; integrin; proteoglycan; receptor; tetraspanin Correspondence H Nagase, Department of Matrix Biology, The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH UK Fax: +44 02083834488 Tel: 02083834994 E-mail: h.nagase@imperial.ac.uk; h.nagase@ic.ac.uk (Received 26 June 2010, revised 15 September 2010, accepted 22 September 2010) Matrix metalloproteinases (MMPs) are a group of structurally related proteolytic enzymes containing a zinc ion in the active site They are secreted from cells or bound to the plasma membrane and hydrolyze extracellular matrix (ECM) and cell surface-bound molecules They therefore play key roles in morphogenesis, wound healing, tissue repair and remodeling in diseases such as cancer and arthritis Although the cell anchored membranetype MMPs (MT-MMPs) function pericellularly, the secreted MMPs have been considered to act within the ECM, away from the cells from which they are synthesized However, recent studies have shown that secreted MMPs bind to specific cell surface receptors, membrane-anchored proteins or cell-associated ECM molecules and function pericellularly at focussed locations This minireview describes examples of cell surface and pericellular partners of MMPs, as well as how they alter enzyme function and cellular behaviour doi:10.1111/j.1742-4658.2010.07918.x Introduction Timely alteration of extracellular matrix (ECM) composition and the pericellular environment is essential in many biological processes such as embryonic development, morphogenesis, cell migration, differentiation, apoptosis and tissue remodeling In diseases such as cancer [1], atheroma, arthritis, neurodegenerative diseases and various connective tissue diseases, these processes become dysregulated Matrix metalloproteinases (MMPs) are pivotal effectors of the cellular microenvironment and modulate cellular activities and tissue structure throughout development and physiological and pathological remodeling [2] All 23 human MMPs harbor signals that direct them to the endoplasmic reticulum and hence to the cell surface or to secretion The extracellular activities of the MMPs are multiple, cleaving not only the components of the ECM, but also many of the bioactive molecules at or around the cell surface Because there is considerable overlap in substrate specificity amongst the MMPs, mechanisms to preclude redundancy exist A number of post-secretory regulations of MMP activities have been described [3] Specific MMPs have greater affinity for specific substrates and the concentrations of the active enzyme and the preferred substrate relative to other substrates may be determinants of efficacy [4] The mechanisms by which cells can regulate their function in a spatial fashion pose intriguing questions and are clearly of critical importance in relation to remodeling events, Abbreviations ECM, extracellular matrix; GPI, glycosylphosphatidylinositol; HB-EGF, heparin-binding epidermal growth factor; LRP, low-density lipoprotein receptor-related protein; MMP, matrix metalloproteinase, MT-MMP, membrane-type matrix metalloproteinase; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase MMPs in the pericellular environment directed cell migration and the directed interactions with other cells Among all the MMPs, six are membrane-type (MT)-MMPs that have specific domains sequestering them at the cell membrane The majority of MMPs are secreted into the extracellular space, although there is accumulating evidence that they may be recruited back to the local cell environment by interactions with cell surface proteins and the pericellular matrix (Table 1) This minireview describes some of the ingenious devices that have been constructed to focus and regulate the proteolytic activity of the MMPs in the pericellular environment MMP domain structure Besides the archetypal secretory signal sequence, regulatory propeptide and catalytic domain, the MMPs have a C-terminal hemopexin-like domain, with the exception of MMP-7, MMP-23 and MMP-26 MMP-2 and MMP-9 also have three repeats of the fibronectin type II motif inserted into the catalytic domain There are six membrane-anchored MMPs, termed ‘membrane-type’ (MT); four are transmembrane proteins with short cytoplasmic domains (MT1-, MT2-, MT3and MT5-MMP) and two with glycosylphosphatidylinositol (GPI) anchors (MT4- and MT6-MMP) [5] Although many studies initially focused on the catalytic domain, particularly in relation to the development of active site inhibitors, it is now appreciated that the extracatalytic domains of the MMPs also play important roles in their function The N-terminal propeptide acts to maintain the latency of the MMPs by the presence of a cysteine residue in the active site coordinated to the catalytic zinc ion [6–9] The activation mechanism (known as the ‘cysteine switch’) involves proteolytic cleavages of the propeptide causing a destabilization of the cysteine–zinc interaction [10] The extra catalytic domains of the MMPs can contribute to macromolecular substrate specificity; the fibronectin type II domains of MMP-2 and MMP-9 are important for the cleavage of denatured collagens, type IV collagen and elastin [11,12] The hemopexin Table Cell surface-binding partners of MMPs Some representative examples of the associations of MMPs with cell surface molecules and the domain involved in interactions are shown It is possible that such interactions confer site specificity for MMP action and could form the basis for therapeutic targeting outside the catalytic cleft MMP Domain Cell surface-binding Reference MMP-1 MMP-2 MMP-2 MMP-2 MMP-2 MMP-2 MMP-3 MMP-7 MMP-7 MMP-7 MMP-8 MMP-9 MMP-9 MMP-9 MMP-9 MMP-9 MMP-9 MMP-9 MMP-13 MMP-14 (MT1-MMP) MMP-14 MMP-14 MMP-14 MMP-14 MMP-15 MMP-16 MMP-16 MMP-24 MMP-25 Linker and Hemopexin Hemopexin Hemopexin Catalytic FN domain ? Hemopexin ? Propeptide Catalytic Pro and active forms Hemopexin Hemopexin Hemopexin Catalytic Hemopexin Not known Linker, hemopexin Not known Hemopexin Not known ?indirect Hemopexin Hemopexin ? Hemopexin Hemopexin Catalytic Hemopexin Hemopexin a2b1 integrin I-domain MT1-MMP:TIMP-2 complex Chondroitin 4-sulfate (cell membrane) b2 integrin LRP-1 Bone sialoprotein (cell surface) Collagen I CD44, syndecans, glypicans (heparan sulfate) CD151 Cholesterol sulfate (cell membrane) Neutrophil surface CD44 Ku dimer (Ku80) b1 integrin b2 integrin b5 integrin I-EGF-like domains and Type VI collagen a2 chain (cell surface) LRP-1 and -2 Receptor ⁄ LRP-1 CD44H stem Claudin CD63 MMP-14 CD151 CD44H CD44H Chondroitin-4-sulfate (cell surface) CD44H CD44H [39,101] [102] [48] [103] [67] [91] [104] [61,62,105] [51] [85] [106] [55,72] [73] [58] [103] [107] [87] [71] [69] [25] [22] [53] [21] [52] [108] [108] [109] [108] [108] FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment G Murphy and H Nagase domain of MMP-2 was found to bind chemokines such as monocyte chemoattractant protein-3 and hence facilitated its cleavage [13] The hemopexin domains of the collagenolytic MMPs (MMP-1, MMP-2, MMP-8, MMP-13 and MT1-MMP) are essential for cleaving native triple helical collagen monomers It has been shown that collagenases locally unwind the triple helix to allow access of the individual a chains to the active site center [14] Hence, the collagen-binding site may be composed of elements from both the catalytic and the hemopexin domains It is also clear that interdomain flexibility is key for the specificity of the collagenases and possibly other MMPs [15] Cell membrane-anchored MMPs Unlike most of the soluble MMPs, membraneanchored MT-MMPs are already active at the cell surface because they are cleaved intracellularly by furinlike proprotein convertases at their specific recognition sequence, RX[R ⁄ K]R, located at the C-terminus of the propeptide [16–18] MT1-MMP is the best studied of this subfamily and is known to promote cell invasion and motility by degrading pericellular ECM molecules and eliciting the ‘shedding’ of CD44 and syndecan1 ectodomains It also degrades a plethora of other extracellular and cell surface proteins [18,19] Importantly, MT1-MMP activates proMMP2 via a mechanism in which the tissue inhibitor of MMPs, tissue inhibitor of metalloproteinase (TIMP)-2, bound to the MT1-MMP catalytic domain acts as a ‘receptor’ for proMMP-2 at the cell surface In this system, modules within blades III and IV of the hemopexin domain of proMMP-2 bind to the C-terminal domain of TIMP-2 and this ternary complex formation allows proteolytic activation of proMMP-2 by an adjacent molecule of MT1-MMP that is free of TIMP-2 MT1-MMP can also activate proMMP-13 [20] It is therefore regarded as one of the key factors influencing the input of the cellular microenvironment into cell signaling pathways [18] Dimerization of MT1-MMP via the hemopexin domain is essential for both collagenolysis and effective proMMP-2 activation and it may be the basis of its function as an oligomer at the cell surface [21] Miyamori et al [22], on the other hand, reported that claudin-5 at endothelial cell tight junctions recruits MT1-MMP and proMMP-2 on the cell surface to achieve elevated focal concentrations, leading to enhanced proMMP-2 activation independent of TIMP-2 Similar enhancements of proMMP-2 activation were reported for other MT-MMPs, suggesting that clustering is an important factor for proMMP-2 activation [22] To achieve focal degradation, cells localize MT1MMP at lamellipodia, the migration front of the cells [23–25] This localization may be achieved by interaction with CD44 and integrins (see below) MMP-2 is also enriched in invadopodia and it has been suggested that it could be bound to MT1-MMP through TIMP-2, as described above MT1-MMP is largely sequestered intracellularly in membrane vesicles and may be derived from newly synthesized material, or from surface enzyme recycled through endocytosis Studies to determine MT1-MMP localization in invading cells are ongoing, although they have identified pathways necessary for the formation of invasive structures and the movement of secretory vesicles involving microtubules and Rab proteins [26–29] The short 20 amino acid cytoplasmic domain of MT1-MMP appears to be of importance in linking the enzyme proteolytic activity to efficient cell migration and invasion; several studies have shown that deletion of this domain markedly reduces cell migration triggered by the enzyme without affecting the cell surface proteolytic activity of the enzyme [30–33] However, there is no universal agreement on this point because, in some over-expression studies, MT1-MMP with the cytoplasmic domain deleted can efficiently drive cell migration through collagen [34] This may be a result of overloading of the secretory pathway with an excess of enzyme, over-riding the normal regulatory mechanisms In the same study, the transmembrane domain was found to be essential because secreted collagenases such as MMP-1 or MT1-MMP without the transmembrane domain did not drive cell invasion through a 3D collagen matrix Membrane-anchoring of either MMP-1, or even the catalytic domain of MT1-MMP alone, could drive collagenolytic migration, albeit with considerably less efficiency than MT1MMP itself [34] Cell invasion through a fibrin gel also required intact membrane tethered MT1-MMP, although the tethered catalytic domain alone was not effective in this case [34] How the hemopexin domain interacts with a fibrin substrate has not been studied Of the other MT-MMPs, only MT2-MMP has been shown to play a similar role to MT1-MMP in cell invasion of collagen I gels [35] Studies looking at cell invasion through intact basement membranes have shown that MT2-MMP and MT3-MMP, as well as MT1-MMP, may have important roles [36] These enzymes can degrade laminin and type IV collagen and the importance of membrane tethering and the lack of requirement for the hemopexin domain for cell invasion were demonstrated The two GPI-anchored members of the MT-MMP family, MT4-MMP and MT6-MMP, have a broad substrate repertoire that is FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase still being defined, including ECM proteins, and have been shown to activate proMMP-2 and proMMP-9 MT4-MMP also activates proADAMTS-4 [37] It is considered that MT4 and MT6-MMP may have unique roles, related to their localization in specific cellular microenvironments via the GPI anchor within lipid rafts of cell membranes [16] GPI-MT-MMP activity at the cell surface is also regulated by endocytosis and recycling, as reported for MT1-MMP [16] There is also some preliminary evidence for homodimerization of the GPI-MT-MMPs, although this has not been studied in depth [16] Integrins Studies of wound healing in keratinocyte monolayers using blocking-antibodies indicated that the proteolytic activity of MMP-1 is required for migration of human keratinocytes on native collagen I Upon wounding, keratinocytes contact dermal collagen I fibrils and the interaction with a2b1 integrin stimulates the cell to produce proMMP-1 [38] Biochemical and cell-based studies have further shown that both proMMP-1 and MMP-1 bind the a2b1 integrin via the I domain of the a2 integrin subunit and that the linker peptide and the hemopexin domain of MMP-1 are required for optimal binding [39] Basal keratinocytes constitutively express the a2b1 integrin on their basolateral surfaces and, in wounds, this receptor accumulates at the forward-basal tip of migrating keratinocyte in contact with dermal type I collagen [38,39] Because the a2b1 integrin binds native collagen I with high affinity, clustering this integrin at contact points would tightly tether resting keratinocytes to the dermis, although MMP-1 bound to a2b1 integrin focally cleaves the collagen matrix This results in denaturation of collagen fragments, which weakens the adhesion to the matrix and allows keratinocyte migration [38,39] Hence, a2b1 integrin, MMP-1 and collagen substrate coordinate together to drive and regulate migrating keratinocyte during re-epithelialization This phenomenon, however, has not been further studied in vivo, probably because MMP-13, the predominant collagenase in mice, does not appear to interact with integrins It is also not known whether a similar system operates in other cell types, although other epithelial cells that move in two dimensions may utilize MMP-1 in a similar way MT1-MMP can be colocalized with b1 integrin in some cell types [40,41], and this appears to regulate its function It is not clear whether this the result of a direct interaction, although these reports suggest that MT1-MMP and b1 integrin are functioning in the same area on the cell surface In ovarian cancer cells, MMPs in the pericellular environment antibody-induced clustering of a3b1 integrin stimulates polarized trafficking and cell surface expression of MT1-MMP, colocalization to aggregated integrin complexes and activation of pro-MMP-2 In the case of endothelial cells, MT1-MMP is up-regulated and colocalizes with b1 integrin at the intercellular contacts of confluent cells on b1 integrin-interacting matrices such as collagen I, fibronectin or fibrinogen This up-regulation was also shown to be the result of an impairment of internalization of the cell surface MT1-MMP [42] On migrating endothelial cells, MT1-MMP was found to be associated with avb3 integrin at motility-associated structures and the two proteins could be co-immunoprecipitated [42] It has also been reported that the integrin avb3 binds MMP-2 via its hemopexin domain [43,44] and it is colocalized with degraded collagen type I [45] Physical interaction of MT1-MMP with avb3 can process the av subunit and increases outside-in signaling via avb3 [46] Furthermore, it is possible that MMP-2 and MT1-MMP activities could be colocalized through their avb3-binding to modify integrin-ligand interactions rapidly in situ [42,47] The isolated hemopexin domain of MMP-2 was reported to block angiogenesis in model systems and to inhibit the interaction of MMP-2 with integrin avb3 [43,44] However, there remains some controversy on the direct binding of avb3 and the MMP-2 hemopexin domain [48,49] Cells expressing avb3 could not use MMP-2 coated surfaces either to attach or spread It is possible that specific forms of the integrin and MMP-2 are involved in binding interactions and that this cannot always be recapitulated in vitro MT1-MMP has been described as interacting with avb8 to activate transforming growth factor (TGF)b1 It has been proposed that, upon ligation of avb8 with latent TGFb (latency associated peptide-b1 ⁄ latency-associated peptide-b1), avb8 and MT1-MMP become closely associated and form a complex on the cell surface [50] The mechanism for this is unknown, although it is postulated that the interaction may be indirect because the cell surface appears to be required for productive interactions and the secreted forms of avb8 and MT1-MMP did not activate TGFb [50] Because the localization of MT1-MMP in latency-associated peptide-b1 substrate contacts is dependent on the presence of b8, it is likely that avb8–latent TGF b interaction initiates the recruitment of MT1-MMP [50] Tetraspanins Tetraspanins are evolutionarily conserved membrane proteins that tend to associate laterally with one FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment G Murphy and H Nagase another and to cluster dynamically with numerous partner proteins in membrane microdomains Consequently, members of this family are involved in the coordination of intracellular and intercellular processes, including signal transduction, cell proliferation, adhesion and migration Recent characterization of tetraspanin-enriched microdomains suggests that they might be specially suited for the regulation of avidity of adhesion receptors and the compartmentalization of enzymatic activities Shiomi et al [51] reported that CD151 binds to the propeptide of proMMP-7 and actives the enzyme on the cell surface It is considered to be the result of conformational changes in proMMP-7 induced by interacting with CD151, thus facilitating a spontaneous activation of proMMP-7 pericellularly The tetraspanin CD151 may also be a key regulator of MT1-MMP function at the surface of endothelial cells MT1-MMP colocalizes with tetraspanin CD151 and its associated partner a3b1 integrin at lateral endothelial cell junctions Biochemical and fluorescence resonance energy transfer analyses by ´ Yanez-Mo et al [52] showed that the MT1-MMP ˜ hemopexin domain associates with CD151 and forms an a3b1 integrin ⁄ CD151 ⁄ MT1-MMP ternary complex Ablation of CD151 expression enhanced MT1-MMPmediated activation of MMP-2, although collagen degradation was reduced around the cell periphery MT1-MMP subcellular localization and its inclusion into detergent-resistant membrane domains, as well as association with the a3b1 integrin, were affected [52] Thus, CD151 can finely regulate not only proteolytic activities of MT1-MMP, but also the sites of action through complex formation with a3b1 Another tetraspanin, CD63, a component of late endosomal and lysosomal membranes, interacts with MT1-MMP directly through the N-terminus of CD63 and the hemopexin domain [53] and accelerates internalization and lysosomal degradation of MT1-MMP [53], thus acting as a further regulator of MT1-MMP trafficking CD44 The hyaluronan receptor CD44, of which some forms are heavily glycosylated and sulfated, is an important mediator of cell migration and tissue remodeling events CD44v(3,8-10) was reported to be associated with active MMP-9 within the invadopodia of metastatic breast cancer cells [54] The complex links to ankyrin and the membrane-associated actomyosin contractile system required for ‘invadopodia’ formation, thus coupling matrix degradation and tumor cell migration during breast cancer progression [54] Yu and Stamenkovic [55] also showed that active MMP-9 can associate with CD44 on mammary carcinoma cells and activate latent TGFb TIMP-1 binding to a proMMP-9–CD44 complex is also a prerequisite for antiapoptotic signaling in erythroid cells [56] RedondoMunoz et al [57] found that CD44v and a4b1integrin colocalize with MMP-9 in invading lymphoid cells, and MMP-9 produced by chronic lymphocytic leukemia B cells is considered to contribute to their tissue infiltration by degrading extracellular and membraneanchored substrates This interaction is mediated by the hemopexin domain Binding of soluble or immobilized MMP-9, or the MMP-9 hemopexin domain, to a4b1 integrin and CD44v prevents B-cell leukemia lymphocyte apoptosis by inducing Lyn activation, STAT3 phosphorylation and Mcl-1 up-regulation [58], although the target(s) of MMP-9 activity in this context are not yet known As discussed above, CD44 also interacts with MT1MMP, and directs the presence of MT1-MMP in lamellipodia of the invasive front of migrating cells [25] This localization may be achieved by interaction with CD44 through the hemopexin domain of the enzyme and stem region of CD44, and CD44 associates with F-actin through its cytoplasmic domain by interacting with Ezrin ⁄ Radixin ⁄ Moesin proteins MT1MMP is also localized to F-actin-rich invasive structures found in some cells, termed invadopodia, and detailed time-lapse studies have demonstrated that cortactin and actin aggregates at membrane regions adherent to matrix where MT1-MMP accumulates [26] Matrix degradation leads to cortactin dissociation from the area, although MT1-MMP remains associated with foci of degraded matrix [26] Hence, proteolytic shedding of CD44 from the cell surface by MT1-MMP promotes cell migration on a hyaluronan based 2D matrix [59] MT1-MMP may therefore act to regulate the adhesion properties of cellular lamellipodia Again, the hemopexin domain of MT1-MMP is required for CD44 shedding and cell migration to occur in this model Marrero-Diaz et al [60] carried out time-lapse confocal microscopy and fluorescence resonance energy transfer imaging of carcinoma cells embedded in a 3D collagen I matrix containing hyaluronan and showed that MT1-MMP interacted with CD44 preferentially at the trailing edge of the invading tumor cells and that the proteolytic processing of the CD44 extracellular domain was enriched in the retracting rear ends It was concluded that the role of MT1-MMP in CD44-mediated tumor-cell invasion is cell retraction, although CD44 is not essential for MT1MMP-mediated invasion into the 3D matrix of hyaluronan-collagen FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase Membrane proteoglycans and glycosaminoglycans Proteoglycans, which contain either heparan sulfate or chondroitin sulfate glycosaminoglycan chains attached to a protein core, are an important class of cell surface and ECM molecules regulating activation and activity of MMPs Many MMPs are bound to tissues through interaction with glycosaminoglycans, and MMP-7 is one of the most tightly bound MMP-7 is often found to be bound to heparan sulfate proteoglycans on or around epithelial cells and in the underlying basement membrane, and it may be released by heparinase digestion [61] When it is bound to heparin, the activity of MMP-7 is greatly enhanced Two putative heparinbinding peptides were identified near the C- and N-terminal regions of proMMP-7, although molecular modeling suggested an extensive binding track crossing multiple peptide strands Evidence was also found for the binding of MMP-2, -9, -13 and -16 [48,61] As suggested by Ra and Parks [4], binding of those MMPs to heparan sulfate in the extracellular space could prevent the loss of secreted enzyme, provide a reservoir of latent enzyme, and facilitate cellular sensing and regulation of enzyme levels Furthermore, binding to the cell surface could position the enzyme for directed proteolytic attack for activation of (or by) other MMPs and for regulation of other cell surface proteins Forms of the hyaluronan receptor CD44 bearing sulfated glycosaminoglycans bind MMP-9, as discussed above Yu et al [62] reported that such forms of CD44 recruit proteolytically active MMP-7 and the substrate heparin-binding epidermal growth factor precursor (proHB-EGF) via the sulfated sugars, forming a complex on the surface of tumor cell line The proHB-EGF within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to cell survival In CD44() ⁄ )) mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired as a result of altered MMP-7 localization and decreased ErbB4 activation in both uterine and mammary epithelia [62] Because MMP-7 is known as an important regulator of many proteolytic events at the cell surface, it is possible that CD44 interaction could be a means of localizing the enzyme to key sites It is likely that charge interactions with sulfated glycosaminoglycans of CD44 are important, although the molecular nature of this is not fully understood Syndecans and glypicans are other examples of membrane associated proteoglycans with highly sulfated glycosaminoglycan chains that regulate cell surface events by interactions with effectors, including MMPs in the pericellular environment growth factors, integrins and proteinase inhibitors Endometrial epithelial cells and carcinoma cells from various tissues bind to active MMP-7 at the cell surface MMP-7-binding could be decreased by interfering with heparan sulfate proteoglycans, and by interacting with TIMP-2 or a synthetic MMP inhibitor The bound MMP-7 remains fully active towards a macromolecular substrate but is resistant to inhibition by TIMP-2 [63] MMP-9 associated with the heparan sulfate chains of the GPI-anchored cell surface proteoglycan glypican of murine colon adenocarcinoma cells [64] This allows the accumulation of MMP-9 on the tips of invasive protrusions of the cells and promotes their motility Treatment of the cells with heparitinase-I or heparin released MMP-9 from the cell surface, which resulted in the suppression of their motility to a level similar to that exhibited by an MMP inhibitor However, the heparan sulfate-interacting domain of MMP-9 is not known Iida et al [48] reported that melonoma cell specific cell surface chondrotin sulfate proteoglycan enhances the activation of proMMP-2 by MT3-MMP and cell invasion in vitro The complex is formed through glycosaminoglycan components interacting with the catalytic domain of MT3-MMP and the hemopexin domain of proMMP-2 This effect was also observed with isolated chondroitin 4-sulfate, but not chondroitin 6-sulfate, hyaluronan or heparin, suggesting that a specific sulfation pattern is important in those reactions Low-density lipoprotein receptor-related protein (LRP) and Ku LRP is a member of the low-density lipoprotein receptor superfamily and a heterodimeric endocytic receptor for a large number of proteins, and also has signaling properties LRP internalizes many diverse ligands, including a2-macroglobulin-proteinase complexes, several serine proteinases, proteinase inhibitors and proteinase–inhibitor complexes [65] MMP-2, MMP-9 and MMP-13 have been reported to be endocytosed by LRP, introducing another level of regulation of pericellular proteolysis by MMPs ProMMP-2 by itself has a relatively low affinity to LRP but forms complexes with either thrombospondin [66] or TIMP-2 [67] that are readily endocytosed by LRP The study of proMMP-2–TIMP-2 complex internalization indicated that both the fibronectin II domain of MMP-2 and TIMP-2 have independent binding sites in LRP, which enhances the uptake of the complex [67] ProMMP-9 is internalized as the proMMP-9–TIMP-1 complex [68] Internalization of MMP-13 is initiated by binding to an unidentified 170 kDa receptor and the enyzme is FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment G Murphy and H Nagase transferred to LRP for internalization and intracellular degradation [69] Troeberg et al [70] reported that TIMP-3, is also internalized by LRP, which also requires a sulfated proteoglycan as a co-receptor The hemopexin domain of MMP-9 contains a binding site for LRP-1 and LRP-2 and these receptors have been implicated in regulating MMP-9 activity [71] The 64 amino acid linker region of MMP-9 between the catalytic and hemopexin domains is heavily O-glycosylated The linker region is required to correctly orient the hemopexin domain for inhibition by TIMP-1 and internalization by LRP-1 and LRP-2, hence regulating active enzyme bioavailability [71,72] Another interesting molecule interacting with MMP-9 on the cell surface is the heterodimeric DNA repair molecule Ku (Ku70 ⁄ Ku80) Ku not only is present in the cytosol and nucleus, but also is found on cell surface of certain cell types Monferran et al [73] reported that MMP-9 is bound to Ku on the leading and tailing edge of the leukemic cell surface and helps the cell to migrate into type IV collagen matrices, indicating the importance of the membrane bound Ku in ECM turnover The interaction of MMP-9 and Ku is mediated by the hemopexin domain of MMP-9 and Ku80 Emmprin Emmprin, CD147 (Basigin) is an important cell surface bound MMP regulator It is a transmembrane glycoprotein with two Ig-like domains [74] It was identified as an MMP-inducer expressed on epithelial cells and is known to enhance cell proliferation and multidrug resistance by promoting hyaluronan synthesis and angiogenesis via the augmentation of vascular endothelial growth factor production [75] It interacts with several molecules including caveolin, cyclophilin 60 and monocarboxylate transporters [75] Although epithelial Emmprin stimulates surrounding stromal cells to produce a number of proMMPs, proMMP-1 was found to interact with Emmprin on human lung carcinoma cells [76], and both proMMP-1 and active MMP-1 bind to Emmprin on glandular epithelium in the human endometrium [77] Although the activity of MMP-1 on the cell surface has not been examined, it may be another way to specifically regulate pericellular collagenolytic activity Endo180 Endo180 was originally identified as constitutively recycling cell surface receptor [78] It was also found as a macrophage mannose receptor type C lectin [79] and as urokinase-type plasminogen activator receptor associated protein [80] It has also been characterized as a collagen-binding and collagen-internalization receptor [81] MT1-MMP was shown to have a critical role in collagen phagocytosis [82] and recent studies by Messaritou et al [83] have demonstrated that Endo180 is a negative regulator of MT1-MMP activity and thus down-regulates MT1-MMP-dependent MMP-2 activation in HT1080 cells Depletion of Endo180 by siRNA led to the accumulation of collagen in the medium as a result of reduced collagen endocytosis, and resulted in the collagen-dependent increase of MT1-MMP activity on the cell surface However, Messaritou et al [83] could not show direct binding of Endo180 and MT1MMP, suggesting that the effect of Endo180 on the regulation of MT1-MMP activity involves another molecule Their study indicates an intricate coordination of collagen clearance in the pericellular environment mediated both collagen internalization and regulated MT1-MMP activity Cholesterol sulfate MMP-7 cleaves many ECM molecules and other proteins in the cellular microenvironment and is considered to have ‘sheddase’ activities comparable with those of the disintegrin MMPs It is known to induce adhesion of colon cancer cells by the cleavage of cell surface proteins, although binding of MMP-7 to cell surface cholesterol sulfate is essential for this activity and the induction of cell aggregation [84] The cholesterol sulfate-binding site has been identified on the opposite side of the catalytic cleft of MMP-7 [85], and it has been proposed that this makes it possible for the enzyme to cleave both cell surface protein substrates and those in the pericellular ECM Pericellular ECM MMP-binding to the extracellular matrix has been noted in many immunohistochemical and biochemical extraction studies and examples of the potential effects of matrix macromolecule association with MMPs on the activity of the latter have been postulated Because many ECM proteins are associated with the cell surface, it is likely that these act as important binding sites and modulators of pericellular proteolysis The gelatinases, MMP-2 and MMP-9, were the first MMPs to be recognized as binding to fibrillar collagens such as type I and their denatured forms within the ECM It was shown that this was effected by a ‘gelatin-binding domain’, consisting of three repeats of the fibronectin type II motif inserted into the catalytic domain FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase [11,86] Subsequently, proMMP-9 and its TIMP-1 complex were shown to bind with high affinity to a number of cell lines via cell surface a2 chain of type IV collagen [87] Binding of pro-MMP-9 to cells does not result in zymogen activation and is not followed by ligand internalization, even after complex formation with TIMP-1 Interestingly, the proenzyme does not bind to secreted triple-helical collagen IV It was proposed that this unique interaction between pro-MMP-9 and a2(IV) may play a role in targeting the zymogen to cell matrix contacts and in the degradation of the collagen IV network Preliminary studies have implicated the gelatin-binding domain of MMP-9 in a2(IV) collagen-binding [88] However, the nature of a2(IV) collagen association to cells is itself not clear Owen et al [89] showed that MMP-9 secreted by activated PMN leucocytes binds to the cell surface by an unknown mechanism Significantly, the bound enzyme is fully functional proteolytically, although is no longer regulated by TIMP-1 or TIMP-2 Bannikov et al [90] found that the gelatinolytic activity of MMP-9 could be detected in situ in tissue sections of term placenta, However, all the enzyme extracted from this tissue was in a proform They found that purified proMMP-9 acquired activity against gelatin substrates, although its propeptide remained intact These results suggest that, although activation of all known MMPs in vitro is accomplished by proteolytic processing of the propeptide, other mechanisms, such as binding to a ligand or to a substrate, may lead to a disengagement of the propeptide from the active center of the enzyme, causing its activation This observation could have implications for the association of other MMPs to cell surface molecules Bone sialoprotein is a member of a family of glycoprotein ligands for integrins and can therefore be cell surface associated Bone sialoprotein has been shown to induce limited gelatinase activity in proMMP-2 without removal of the propeptide and to restore enzymatic activity to MMP-2 previously inhibited by TIMP-2 [91] More recently Freise et al [87] found that proforms of MMPs were closely associated with collagenous septae in fibrotic liver tissue and that the triple helical domain of a2 chain of collagen VI bound with nanomolar affinity to procollagenases (proMMP-1, -8 and -13) and proMMP-3, as well as proMMP-2 and -9 The binding of collagen VI to those zymogens or activated MMPs reduced the levels of auto-activation and enzymatic activities, respectively, with the exception of an observed increase in proMMP-2 activation and MMP-2 activity It was suggested that the a2(VI) chain modulates MMP availability by sequestering proMMPs in the ECM and blocking proteolytic activity Using MMPs in the pericellular environment tandem affinity expression tagged MMP-13 hingehemopexin domains as a bait, Zhang et al [92] found that they bound TIMP-1 and a2-macroglobulin, fibronectin, type VI collagen, xylosyltransferase 1, decorin, syndecan and serglycin in the medium of human chondrocytes in culture Although the consequences of these interactions remain to be demonstrated, studies suggest that MMP-13 activity may be either targeted at a more specific site in the connective tissue matrix, or that matrix proteins may regulate its activity during cartilage degradation The mechanisms of interaction of the collagenases with fibrillar collagen substrates is key to directed cleavage As exemplified with MT1-MMP, cell surface collagenolysis is implicated in directional cell movement along the collagen fibrils In the tissue, interstitial collagen forms insoluble fibrils that are highly resistant to digestion, even by collagenases such as MMP-1, MMP-13 and MT1-MMP This may be particularly a result of collagenase cleavage sites in collagen fibrils being covered mainly by the C-terminal telopeptide of the neighboring collagen molecule, as shown in the 3D structure of rat tendon collagen fibrils recently solved using X-ray diffraction analysis [93,94] This suggests that the removal of the C-telopeptide or its structural alteration needs to take place before collagenase can act on collagen fibrils This would also remove important cross linking sites from the fibrils On the other hand, Saffarian et al [95] reported that active MMP-1 moves to one direction on collagen fibrils analgous to a molecular ratchet, which is driven by proteolysis This directional movement may be explained by the Orgel model of collagen fibrils [93]: upon destabilization or cleavage of the C-telopeptide, collagenase can remove the C-terminal ¼ fragment including the C-telopeptide, which then exposes the C-terminally adjacent collagenase-cleavage site Subsequent cleavage of this site will expose another site on the C-terminal side Such directional movement of the collagenase may promote cells to move in one direction when the enzyme is attached to the cell surface This may also occur with MT-MMPs and MMP-1 attached to Emmprin or a2b1 integrin Cells such as inflammatory cells may use such a mechanism to move along one direction depending on the orientation of collagen fibrils In Orgel’s model, the a2b1 integrin-binding site in collagen I is also blocked by the adjacent collagen molecule [96] To make these sites available to the integrins, collagenolysis and denaturation of the ¾ fragment is probably necessary Further investigations are necessary to determine how pericellular collagenolysis and integrin engagement are coordinated during the cell movement on collagen fibrils Those questions may apply to the FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment G Murphy and H Nagase migration of many cell types, including cancer cells, inflammatory cells, smooth muscle cells and endothelial cells, as well as the directionality of collagen fibres in the tissue Conclusions and future prospects Subsequent to the discovery of vertebrate collagenase in the tadpole tail undergoing metamorphosis [97], MMPs have largely been characterized in relation to their respective abilities to degrade ECM molecules However, for the last two decades, researchers have recognized that non-ECM proteins, such as serpins, cytokines, chemokines, growth factors and growth factor-binding proteins, are also MMP substrates [2] Along with the cryptic function of ECM molecules exposed by MMP cleavage, these observations emphasize that MMPs play diverse roles in many cellular activities, such as proliferation, differentiation, migration and apoptosis The proteolytic actions associated with these events most effectively occur at or close to the cell surface Thus, the MT-MMPs have been regarded as prime candidates in such activities [19] However, numerous studies have demonstrated that secreted MMPs are also recruited to the cell surface, interacting with cell surface receptors or pericellular macromolecules, including those of the ECM (Table 1) Such interactions introduce intricate regulatory mechanisms that create gradients or directionality of proteolytic activity Of particular note is the role of interacting proteins in endocytic mechanisms to downregulate MMP function Although only a few MMPs have been so far studied, the diversity of mechanisms is proving to be enormous These examples have led us to consider that many, if not all, of the MMPs may frequently function pericellularly, rather than at sites distal to the cells, where the communication between the cells and the surrounding ECM and other bioactive molecules takes place For example, MMP-19 is another member found to be associated with myeloid cell surface, although the binding partner is yet to be identified [98] Identification of the partner molecule would help us understand the role of MMP-19 in blood-derived cell migration Careful immunocytochemical studies of more recently discovered MMPs certainly deserve further attention, which may help to elucidate the molecular mechanism of the proposed function or introduce new biological functions The use of modern techniques for protein identification will also further the characterization of proteins that interact with MMPs [99,100] and further define cell surface focussing and regulation of their function in relation to specific cellular activities 10 Acknowledgements We would like to thank all the individuals who have contributed to MMP research and apologize that we have been unable to cite all the relevant studies in this minireview Our work is supported by grants from Cancer Research UK, Medical Research Council, European Union Framework Program to G.M., the Wellcome Trust, Arthritis Research UK and National Institutes of Health (AR40994) to H.N References Gialeli C, Theocharis AD & Karamanos NK (2010) Metalloproteinases in health and disease: roles of matrix metalloproteinases in cancer progression and their pharmacological targeting FEBS J 278, 16–27 Murphy G & Nagase H (2008) Progress in matrix metalloproteinase research Mol Aspects Med 29, 290– 308 Hadler- Olsen EFB, Sylte I, Uhlin-Hansen L & Winberg J-O (2010) Metalloproteinases in health and disease: regulation of matrix metalloproteinase activity FEBS J 278, 28–45 Ra HJ & Parks WC (2007) Control of matrix metalloproteinase catalytic activity Matrix Biol 26, 587–596 Nagase H, Visse R & Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs Cardiovasc Res 69, 562–573 Becker JW, Marcy AI, Rokosz LL, Axel MG, Burbaum JJ, Fitzgerald PM, Cameron PM, Esser CK, Hagmann WK, Hermes JD et al (1995) Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme Protein Sci 4, 1966–1976 Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G & Tryggvason K (1999) Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed Science 284, 1667– 1670 Elkins PA, Ho YS, Smith WW, Janson CA, D’Alessio KJ, McQueney MS, Cummings MD & Romanic AM (2002) Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase Acta Crystallogr D Biol Crystallogr 58, 1182–1192 Jozic D, Bourenkov G, Lim NH, Visse R, Nagase H, Bode W & Maskos K (2005) X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding J Biol Chem 280, 9578–9585 10 Van Wart HE & Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase 11 12 13 14 15 16 17 18 19 20 21 22 23 matrix metalloproteinase gene family Proc Natl Acad Sci USA 87, 5578–5582 Murphy G, Nguyen Q, Cockett MI, Atkinson SJ, Allan JA, Knight CG, Willenbrock F & Docherty AJP (1994) Assessment of the role of the fibronectin-like domain of gelatinase A by analysis of a deletion mutant J Biol Chem 269, 6632–6636 Shipley JM, Doyle GAR, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG & Senior RM (1996) The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases J Biol Chem 271, 4335–4341 McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I & Overall CM (2000) Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 Science 289, 1202–1206 Chung L, Dinakarpandian D, Yoshida N, LauerFields JL, Fields GB, Visse R & Nagase H (2004) Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis EMBO J 23, 3020–3030 Sela-Passwell N, Rosenblum G, Shoham T & Sagi I (2010) Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? Biochim Biophys Acta 1803, 29–38 Sohail A, Sun Q, Zhao H, Bernardo MM, Cho JA & Fridman R (2008) MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-anchored matrix metalloproteinases: properties and expression in cancer Cancer Metastasis Rev 27, 289–302 ´ Zucker S, Pei D, Cao J & Lopez-Otı´ n C (2003) Membrane type-matrix metalloproteinases (MT-MMP) Curr Top Dev Biol 54, 1–74 Itoh Y & Seiki M (2006) MT1-MMP: a potent modifier of pericellular microenvironment J Cell Physiol 206, 1–8 Barbolina MV & Stack MS (2008) Membrane type 1matrix metalloproteinase: substrate diversity in pericellular proteolysis Semin Cell Dev Biol 19, 24–33 Knauper V, Bailey L, Worley JR, Soloway P, ă Patterson ML & Murphy G (2002) Cellular activation of proMMP-13 by MT1-MMP depends on the C-terminal domain of MMP-13 FEBS Lett 532, 127– 130 Itoh Y, Ito N, Nagase H, Evans RD, Bird SA & Seiki M (2006) Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1MMP Mol Biol Cell 17, 5390–5399 Miyamori H, Takino T, Kobayashi Y, Tokai H, Itoh Y, Seiki M & Sato H (2001) Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases J Biol Chem 276, 28204–28211 Sato H, Okada Y & Seiki M (1997) Membrane-type matrix metalloproteinases (MT-MMPs) in cell invasion Thromb Haemost 78, 497–500 FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment 24 Itoh Y, Takamura A, Ito N, Maru Y, Sato H, Suenaga N, Aoki T & Seiki M (2001) Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion EMBO J 20, 4782–4793 25 Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I & Seiki M (2002) CD44 directs membrane-type matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain EMBO J 21, 3949–3959 26 Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM & Mueller SC (2006) Dynamic interactions of cortactin and membrane type matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function Cancer Res 66, 3034–3043 27 Poincloux R, Lizarraga F & Chavrier P (2009) Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia J Cell Sci 122, 3015–3024 28 Clark ES & Weaver AM (2008) A new role for cortactin in invadopodia: regulation of protease secretion Eur J Cell Biol 29 Bravo-Cordero JJ, Marrero-Diaz R, Megı´ as D, Genı´ s L, Garcı´ a-Grande A, Garcı´ a MA, Arroyo AG & Montoya MC (2007) MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway EMBO J 26, 1499–1510 30 Gingras D, Bousquet-Gagnon N, Langlois S, ´ Lachambre MP, Annabi B & Beliveau R (2001) Activation of the extracellular signal-regulated protein kinase (ERK) cascade by membrane-type-1 matrix metalloproteinase (MT1-MMP) FEBS Lett 507, 231– 236 ´ 31 Langlois S, Gingras D & Beliveau R (2004) Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation Blood 103, 3020–3028 32 Lehti K, Valtanen H, Wickstrom S, Lohi J & ă Keski-Oja J (2000) Regulation of membrane-type-1 matrix metalloproteinase activity by its cytoplasmic domain J Biol Chem 275, 15006–15013 33 Sakamoto T & Seiki M (2009) Cytoplasmic tail of MT1MMP regulates macrophage motility independently from its protease activity Genes Cells 14, 617–626 34 Li XY, Ota I, Yana I, Sabeh F & Weiss SJ (2008) Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase Mol Biol Cell 19, 3221–3233 35 Hotary K, Allen E, Punturieri A, Yana I & Weiss SJ (2000) Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and J Cell Biol 149, 1309–1323 11 MMPs in the pericellular environment G Murphy and H Nagase 36 Hotary K, Li XY, Allen E, Stevens SL & Weiss SJ (2006) A cancer cell metalloprotease triad regulates the basement membrane transmigration program Genes Dev 20, 2673–2686 37 Gao G, Plaas A, Thompson VP, Jin S, Zuo F & Sandy JD (2004) ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1 J Biol Chem 279, 10042– 10051 38 Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG & Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix J Cell Biol 137, 1445–1457 39 Dumin JA, Dickeson SK, Stricker TP, BhattacharyyaPakrasi M, Roby JD, Santoro SA & Parks WC (2001) Pro-collagenase-1 (matrix metalloproteinase-1) binds the a2b1 integrin upon release from keratinocytes migrating on type I collagen J Biol Chem 276, 29368– 29374 40 Ellerbroek SM, Wu YI, Overall CM & Stack MS (2001) Functional interplay between type I collagen and cell surface matrix metalloproteinase activity J Biol Chem 276, 24833–24842 41 Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Brocker EB & Friedl ă P (2003) Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis J Cell Biol 160, 267–277 ´ ´ ´ ˜ ´ ´ 42 Galvez BG, Matı´ as-Roman S, Yanez-Mo M, SanchezMadrid F & Arroyo AG (2002) ECM regulates MT1MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells J Cell Biol 159, 509521 43 Brooks PC, Stromblad S, Sanders LC, Von ă Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP & Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin avb3 Cell 85, 683–693 44 Brooks PC, Silletti S, Von Schalscha TL, Friedlander M & Cheresh DA (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity Cell 92, 391400 45 Petitclerc E, Stromblad S, Von Schalscha TL, ă Mitjans F, Piulats J, Montgomery AM, Cheresh DA & Brooks PC (1999) Integrin alpha(v)beta3 promotes M21 melanoma growth in human skin by regulating tumor cell survival Cancer Res 59, 2724–2730 46 Deryugina EI, Ratnikov BI, Postnova TI, Rozanov DV & Strongin AY (2002) Processing of integrin alpha(v) 12 47 48 49 50 51 52 53 54 55 subunit by membrane type matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase J Biol Chem 277, 9749–9756 ´ ´ ´ Galvez BG, Matı´ as-Roman S, Albar JP, SanchezMadrid F & Arroyo AG (2001) Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling J Biol Chem 276, 37491–37500 Iida J, Wilhelmson KL, Ng J, Lee P, Morrison C, Tam E, Overall CM & McCarthy JB (2007) Cell surface chondroitin sulfate glycosaminoglycan in melanoma: role in the activation of pro-MMP-2 (pro-gelatinase A) Biochem J 403, 553–563 Nisato RE, Hosseini G, Sirrenberg C, Butler GS, Crabbe T, Docherty AJ, Wiesner M, Murphy G, Overall CM, Goodman SL et al (2005) Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical Cancer Res 65, 9377–9387 Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC & Nishimura SL (2002) The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMPdependent activation of TGF-beta1 J Cell Biol 157, 493–507 Shiomi T, Inoki I, Kataoka F, Ohtsuka T, Hashimoto G, Nemori R & Okada Y (2005) Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151 Lab Invest 85, 1489–1506 ´ Yanez-Mo M, Barreiro O, Gonzalo P, Batista A, ˜ ´ Megı´ as D, Genı´ s L, Sachs N, Sala-Valdes M, Alonso MA, Montoya MC et al (2008) MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells Blood 112, 3217–3226 Takino T, Miyamori H, Kawaguchi N, Uekita T, Seiki M & Sato H (2003) Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type matrix metalloproteinase Biochem Biophys Res Commun 304, 160–166 Bourguignon LY, Gunja-Smith Z, Iida N, Zhu HB, Young LJ, Muller WJ & Cardiff RD (1998) CD44v3,8-10 is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells J Cell Physiol 176, 206–215 Yu Q & Stamenkovic I (1999) Localization of matrix metalloproteinase to the cell surface provides a mechanism for CD44-mediated tumor invasion Genes Dev 13, 35–48 FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase ´ 56 Lambert E, Bridoux L, Devy J, Dasse E, Sowa ML, ` Duca L, Hornebeck W, Martiny L & PetitfrereCharpentier E (2009) TIMP-1 binding to proMMP9 ⁄ CD44 complex localized at the cell surface promotes erythroid cell survival Int J Biochem Cell Biol 41, 1102–1115 57 Redondo-Munoz J, Ugarte-Berzal E, Garcı´ a-Marco ˜ JA, del Cerro MH, Van den Steen PE, Opdenakker G, Terol MJ & Garcı´ a-Pardo A (2008) Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B ⁄ MMP-9 in chronic leukemic but not in normal B cells Blood 112, 169– 178 58 Redondo-Munoz J, Ugarte-Berzal E, Terol MJ, Van ˜ ´ den Steen PE, Hernandez del Cerro M, Roderfeld M, Roeb E, Opdenakker G, Garcı´ a-Marco JA & Garcı´ aPardo A (2010) Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain Cancer Cell 17, 160–172 59 Kajita M, Itoh Y, Chiba T, Mori H, Okada A, Kinoh H & Seiki M (2001) Membrane-type matrix metalloproteinase cleaves CD44 and promotes cell migration J Cell Biol 153, 893–904 60 Marrero-Diaz R, Bravo-Cordero JJ, Megı´ as D, Garcı´ a ´ MA, Bartolome RA, Teixido J & Montoya MC (2009) Polarized MT1-MMP-CD44 interaction and CD44 cleavage during cell retraction reveal an essential role for MT1-MMP in CD44-mediated invasion Cell Motil Cytoskeleton 66, 48–61 61 Yu WH & Woessner JF Jr (2000) Heparan Sulfate Proteoglycans as Extracellular Docking Molecules for Matrilysin (Matrix Metalloproteinase 7) J Biol Chem 275, 4183–4191 62 Yu WH, Woessner JF Jr, McNeish JD & Stamenkovic I (2002) CD44 anchors the assembly of matrilysin ⁄ MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling Genes Dev 16, 307– 323 63 Berton A, Selvais C, Lemoine P, Henriet P, Courtoy PJ, Marbaix E & Emonard H (2007) Binding of matrilysin-1 to human epithelial cells promotes its activity Cell Mol Life Sci 64, 610–620 64 Koyama Y, Naruo H, Yoshitomi Y, Munesue S, Kiyono S, Kusano Y, Hashimoto K, Yokoi T, Nakanishi H, Shimizu S et al (2008) Matrix metalloproteinase-9 associated with heparan sulfate chains of GPI-anchored cell surface proteoglycans mediates motility of murine colon adenocarcinoma cells J Biochem 143, 581–592 65 Herz J & Strickland DK (2001) LRP: a multifunctional scavenger and signaling receptor J Clin Invest 108, 779–784 66 Yang Z, Strickland DK & Bornstein P (2001) Extracellular Matrix Metalloproteinase levels are regulated FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS MMPs in the pericellular environment 67 68 69 70 71 72 73 74 75 76 77 by the Low DensityLlipoprotein-related scavenger receptor an thrombospondin J Biol Chem 276, 8403–8408 Emonard H, Belton G, Troeberg L, Berton A, Robinet A, Henriet P, Marbaix E, Kirkegaard K, Patthy L, Eeckhout Y et al (2004) Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanism J Biol Chem 279, 54944–54951 Hahn-Dantona E, Ruiz JF, Bornstein P & Strickland DK (2001) The Low Density Lipoprotein Receptorrelated Protein Modulates Levels of Matrix Metalloproteinase (MMP-9) by Mediating Its Cellular Catabolism J Biol Chem 276, 15498–15503 Barmina OY, Walling HW, Fiacco GJ, Freije JM, ´ Lopez-Otı´ n C, Jeffrey JJ & Partridge NC (1999) Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization J Biol Chem 274, 30087–30093 Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P & Nagase H (2008) Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases FASEB J 22, 3515–3524 Van den Steen PE, Van Aelst I, Hvidberg V, Piccard H, Fiten P, Jacobsen C, Moestrup SK, Fry S, Royle L, Wormald MR et al (2006) The hemopexin and O-glycosylated domains tune gelatinase B ⁄ MMP-9 bioavailability via inhibition and binding to cargo receptors J Biol Chem 281, 18626–18637 Piccard H, Van den Steen PE & Opdenakker G (2007) Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins J Leukoc Biol 81, 870–892 Monferran S, Paupert J, Dauvillier S, Salles B & Muller C (2004) The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase Embo J 23, 3758–3768 Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H & Nabeshima K (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily Cancer Res 55, 434–439 Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J & Kikuchi M (2006) Emmprin (basigin ⁄ CD147): matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression Pathol Int 56, 359–367 Guo HM, Li RS, Zucker S & Toole BP (2000) EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface Cancer Res 60, 888–891 Noguchi Y, Sato T, Hirata M, Hara T, Ohama K & Ito A (2003) Identification and characterization of extracellular matrix metalloproteinase inducer in 13 MMPs in the pericellular environment 78 79 80 81 82 83 84 85 86 87 88 89 90 14 G Murphy and H Nagase human endometrium during the menstrual cycle in vivo and in vitro J Clin Endocrinol Metab 88, 6063–6072 Isacke CM, van der GP, Hunter T & Trowbridge IS (1990) p180, a novel recycling transmembrane glycoprotein with restricted cell type expression Mol Cell Biol 10, 2606–2618 Wu K, Yuan J & Lasky LA (1996) Characterization of a novel member of the macrophage mannose receptor type C lectin family J Biol Chem 271, 21323– 21330 Behrendt N, Jensen ON, Engelholm LH, Mortz E, Mann M & Dano K (2000) A urokinase receptor-associated protein with specific collagen binding properties J Biol Chem 275, 1993–2002 Leitinger B & Hohenester E (2007) Mammalian collagen receptors Matrix Biol 26, 146–155 Lee H, Overall CM, McCulloch CA & Sodek J (2006) A critical role for the membrane-type matrix metalloproteinase in collagen phagocytosis Mol Biol Cell 17, 4812–4826 Messaritou G, East L, Roghi C, Isacke CM & Yarwood H (2009) Membrane type-1 matrix metalloproteinase activity is regulated by the endocytic collagen receptor Endo180 J Cell Sci 122, 4042–4048 Yamamoto K, Higashi S, Kioi M, Tsunezumi J, Honke K & Miyazaki K (2006) Binding of active matrilysin to cell surface cholesterol sulfate is essential for its membrane-associated proteolytic action and induction of homotypic cell adhesion J Biol Chem 281, 9170–9180 Higashi S, Oeda M, Yamamoto K & Miyazaki K (2008) Identification of amino acid residues of matrix metalloproteinase-7 essential for binding to cholesterol sulfate J Biol Chem 283, 35735–35744 Xu X, Chen Z, Wang Y, Yamada Y & Steffensen B (2005) Functional basis for the overlap in ligand interactions and substrate specificities of matrix metalloproteinases-9 and -2 Biochem J 392, 127–134 Freise C, Erben U, Muche M, Farndale R, Zeitz M, Somasundaram R & Ruehl M (2009) The alpha chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity Matrix Biol 28, 480– 489 Olson MW, Toth M, Gervasi DC, Sado Y, Ninomiya Y & Fridman R (1998) High affinity binding of latent matrix metalloproteinase-9 to the a2(IV) chain of collagen IV J Biol Chem 273, 10672–10681 Owen CA, Hu Z, Barrick B & Shapiro SD (2003) Inducible expression of tissue inhibitor of metalloproteinases-resistant matrix metalloproteinase-9 on the cell surface of neutrophils Am J Respir Cell Mol Biol 29, 283–294 Bannikov GA, Karelina TV, Collier IE, Marmer BL & Goldberg GI (2002) Substrate binding of gelatinase B 91 92 93 94 95 96 97 98 99 100 101 102 103 induces its enzymatic activity in the presence of intact propeptide J Biol Chem 277, 16022–16027 Jain A, Fisher LW & Fedarko NS (2008) Bone sialoprotein binding to matrix metalloproteinase-2 alters enzyme inhibition kinetics Biochemistry 47, 5986– 5995 Zhang L, Yang M, Yang D, Cavey G, Davidson P & Gibson G (2010) Molecular interactions of MMP-13 C-terminal domain with chondrocyte proteins Connect Tissue Res 51, 230–239 Orgel JP, Irving TC, Miller A & Wess TJ (2006) Microfibrillar structure of type I collagen in situ Proc Natl Acad Sci USA 103, 9001–9005 Perumal S, Antipova O & Orgel JP (2008) Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis Proc Natl Acad Sci USA 105, 2824–2829 Saffarian S, Collier IE, Marmer BL, Elson EL & Goldberg G (2004) Interstitial collagenase is a Brownian ratchet driven by proteolysis of collagen Science 306, 108–111 Sweeney SM, Orgel JP, Fertala A, McAuliffe JD, Turner KR, Di Lullo GA, Chen S, Antipova O, Perumal S, Ala-Kokko L et al (2008) Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates J Biol Chem 283, 21187–21197 Gross J & Lapiere CM (1962) Collagenolytic activity in amphibian tissues: a tissue culture assay Proc Natl Acad Sci USA 48, 1014–1022 Mauch S, Kolb C, Kolb B, Sadowski T & Sedlacek R (2002) Matrix metalloproteinase-19 is expressed in myeloid cells in an adhesion-dependent manner and associates with the cell surface J Immunol 168, 1244– 1251 Overall CM & Blobel CP (2007) In search of partners: linking extracellular proteases to substrates Nat Rev Mol Cell Biol 8, 245–257 Tomari T, Koshikawa N, Uematsu T, Shinkawa T, Hoshino D, Egawa N, Isobe T & Seiki M (2009) High throughput analysis of proteins associating with a proinvasive MT1-MMP in human malignant melanoma A375 cells Cancer Sci 100, 1284–1290 Stricker TP, Dumin JA, Dickeson SK, Chung L, Nagase H, Parks WC & Santoro SA (2001) Structural analysis of the alpha Integrin I domain ⁄ procollagenase-1 (matrix metalloproteinase-1) interaction J Biol Chem 276, 29375–29381 Patterson ML, Atkinson SJ, Knauper V & Murphy G ă (2001) Specic collagenolysis by gelatinase A, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain FEBS Lett 503, 158–162 Stefanidakis M, Bjorklund M, Ihanus E, Gahmberg CG & Koivunen E (2003) Identification of a negatively charged peptide motif within the catalytic FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS G Murphy and H Nagase domain of progelatinases that mediates binding to leukocyte beta integrins J Biol Chem 278, 34674– 34684 104 Allan JA, Hembry RM, Angal S, Reynolds JJ & Murphy G (1991) Binding of latent and high Mr active forms of stromelysin to collagen is mediated by the C-terminal domain J Cell Sci 99, 789–795 105 Ra HJ, Harju-Baker S, Zhang F, Linhardt RJ, Wilson CL & Parks WC (2009) Control of promatrilysin (MMP7) activation and substrate-specific activity by sulfated glycosaminoglycans J Biol Chem 284, 27924–27932 ´ 106 Owen CA, Hu Z, Lopez-Otı´ n C & Shapiro SD (2004) Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue MMPs in the pericellular environment inhibitor of metalloproteinase-resistant collagenase and serpinase J Immunol 172, 7791–7803 107 Bjorklund M, Heikkila P & Koivunen E (2004) Peptide inhibition of catalytic and noncatalytic activities of matrix metalloproteinase-9 blocks tumor cell migration and invasion J Biol Chem 279, 29589–29597 108 Suenaga N, Mori H, Itoh Y & Seiki M (2005) CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type matrix metalloproteinase Oncogene 24, 859–868 109 Iida J, Pei D, Kang T, Simpson MA, Herlyn M, Furcht LT & McCarthy JB (2001) Melanoma chondroitin sulfate proteoglycan regulates matrix metalloproteinase-dependent human melanoma invasion into type I collagen J Biol Chem 276, 18786–18794 FEBS Journal 278 (2011) 2–15 ª 2010 The Authors Journal compilation ª 2010 FEBS 15 ... MMP-1 bind the a2b1 integrin via the I domain of the a2 integrin subunit and that the linker peptide and the hemopexin domain of MMP-1 are required for optimal binding [39] Basal keratinocytes... to cell matrix contacts and in the degradation of the collagen IV network Preliminary studies have implicated the gelatin-binding domain of MMP-9 in a2(IV) collagen-binding [88] However, the nature... It is therefore regarded as one of the key factors in? ??uencing the input of the cellular microenvironment into cell signaling pathways [18] Dimerization of MT1-MMP via the hemopexin domain is