Mechanisms for pro matrix metalloproteinase activation

Mechanisms for pro matrix metalloproteinase activation Review article

GILLIAN MURPHY, HEATHER STANTON, SUSAN COWELL,' GEORGINA BUTLER, VERA KNAUPER, SUSAN ATKINSON and JELENA GAVRILOVIC

School of Biological Sciences, University of East Anglia, Norwich, UK. and 'Strangeways Research Laboratory, Cambridge. UK

Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S & Gavrilovic J. Mechanisms for pro matrix metalloproteinase activation. APMIS 1999;107:3844.

The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of regulation of these proteinases. Potential physiological mechanisms including cell-associated plasmin generation by urokinase-like plasminogen activator, or the action of cell surface MTI-MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A, collagenase 3 and gelatinase B may be activated by MT-MMP based mechanisms, as evidenced by both biochemical and cell based studies. Hence the regulation of MT-MMPs themselves becomes critical to the determination of MMP activity. This includes activation, assembly at the cell surfaces as TIMP-2 complexes and subsequent inactivation by proteolysis or TIMP inhibition.

Key words: Matrix metalloproteinase; TIMP: activation.

Gillian Murphy, School of Biological Sciences, University of East Anglia, Norwich. UK.

Proteolysis of the extracellular matrix (ECM) is not only a feature of the structural remodelling associated with repair instigated by disease processes, but is also as a component of the cell-cell and cell-ECM interactions underlying developmental events. The role of matrix metalloproteinases (MMPs) in matrix turnover has long been under study, and it has be- come evident that their activities are critical, necessit- ating several levels of regulation in vivo. Most MMPs are not present at high levels in normal tissues and their expression is tightly regulated by growth factors and cytokines when remodelling does occur. The MMPs are generally secreted into the extracellular environment as inactive proenzymes, an important level of regulation of their activity then being their conversion to the active form by proteolytic removal of the propeptide. Association of MMPs with the cell surface or ECM components modulates their re- lationship with substrates, activators and inhibitors, acting as further levels for the regulation of their activity.

A number of cell model studies have demonstrated that MMP activation can occur at the cell surface

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through the uPAluPARlplasminogen cascade for plasmin generation ( I , 2) and activation by plasmin has been extensively studied biochemically. This is thought to be of potential physiological importance and a pericellular activation cascade may be established which consists of serine proteinases and MMPs being tightly regulated by plasniinogen activator and plasmin inhibitors as well as tissue inhibitors of metalloproteinases (TIMPs).

The more recent discovery of four membrane associated MMPs (membrane type. MT-MMPs) has strengthened the concept of pericellular activation cascade mechanisms for the MMPs. I t has been shown that three MT-MMPs can activate progelatinase A, which has a propeptide that is not generally susceptible to proteolytic initiation of activation by serine proteinases (3). MTI-MMP can also activate procollagenase-3 (MMP-I 3) and the potential for interaction with other activation cascades has been demonstrated (4-6). MT-MMPs also have direct proteolytic activity against extracellular matrix conipo- nents (7, 8). Regulated pericellular proteolysis may not therefore be confined to the uPA system. since

PRO MATRIX METALLOPROTEINASE ACTIVATION

p i q t - proMMP-9

aMMP-2

Fig. 1. Matrix metalloproteinase activation cascades. Cell surface associated plasmin. generated by the activity of receptor bound urokinase-like plasminogen activator on cell bound plasminogen, is a key initiator of matrix metalloproteinase activation. notably stromelysin-I, MMP3 and gelatinase B. MMP9. Active cell surface MTI-MMP acts as a second focus of activation. cleaving gelatinase A, MMP2 to potentiate further self-cleavage reactions. MTI-MMP may also activate collagenase 3. MMP13 directly. A more likely event. is activation of MMP13 by MMP2. Both MMP2, MMP3 and MMP13 can activate MMP9. MMP13 may also be activated by MMP3. Not shown, plasmin and MMP3 are responsible for the activation of collagenase 1, MMPI. The activation of proMMPs is largely limited to the pericellular environment where cell associated proteinases can function in a privileged environment away from an excess of proteinase inhibitors. The generation of partially active or active MMPs allows a cascade of cleavages to generate fully active enzymes. The efficiency of these interactions is dependent upon mechanisms for the concentration of MMPs at the cell surface or on the extracellular matrix.

studies on the MT-MMPs are now showing that anal- ogous complex mechanisms based on these enzymes exist for the cell surface amplification of proteolytic activity (Fig. I ) .

ACTIVATION OF GELATINASE A BY MTI-MMP

Progelatinase A activation by cells expressing MTl- MMP at their surface involves a two step activation mechanism. An initial cleavage was observed at the A ~ n ' ~ - L e u ' ~ peptide bond, due to MTI-MMP mediated proteolysis in a region of the progelatinase A propeptide domain which is solvent exposed, referred to as the propeptide bait region (9,lO). The secondary cleavage event was due to autoproteolytic cleavage, since an inactive progelatinase A mutant ( ~ ~ o E ~ ~ ~ - A gelatinase A) was only processed by MT-MMP to the A~n"-Leu'~ intermediate form. Processing by MTI - MMP or MT2-MMP was inhibited by either TIMP- 2 or TIMP-3 in a concentration dependent fashion, while TIMP-I was not effective under the same con- ditions (9-1 I ) . The process appears to involve binding of the proenzyme to an MTI-MMP/TIMP-2 complex ("receptor") on the cell surface, through in-

teraction between the C-terminal domain of progelatinase A and the C-terminal domain of TIMP-2 (9, 12-1 5). By establishing a trimolecular complex, con- sisting of MTl-MMP/TIMP-2/progelatinase A, as demonstrated by cross-linking experiments ( 1 5) the components are concentrated on the cell surface. Pro- cessing of progelatinase A to the L e d 8 intermediate form may then be initiated by an adjacent free and active MT1-MMP molecule. This initial cleavage event destabilises the structure of the progelatinase A propeptide domain and autoproteolysis then pro- ceeds in a gelatinase A concentration dependent manner, which releases the rest of the propeptide domain and fully active gelatinase A. In cell culture studies, the enzyme concentration in solution is low and deletion of either the progelatinase A C-terminal domain or the transmembrane domain of MTI- MMP abolishes progelatinase A activation, empha- sising that the binding mechanism involving the MTl-MMP/TIMP-2 complex on the cell surface acts as a concentration mechanism which is crucial for the efficiency of activation (9, 12, 13, 16, 17). It appears that addition of small amounts of TIMP-2 to cells expressing MT 1-MMP can enhance progelatinase A activation, since this increased the concentration of the MTl-MMP/TIMP-2 receptor for progelatinase A on the cell surface (15-18). However, at high TIMP- 2 concentrations all the MTl-MMP molecules on the cell surface are complexed with TIMP-2 and, al- though progelatinase A binding occurs, no active MTl -MMP remains to initiate processing. This concept has been substantiated by cell free kinetic studies of the effects of the MTl-MMPiTIMP-2 'receptor' as a mode of concentrating progelatinase A in order to promote autoproteolysis (19). This suggests that progelatinase A activation is regulated by the amount of TIMP-2 secreted by MTl-MMP expressing cells as well as by the extent of MTI-MMP activation. In addition, if high concentrations of TIMP-3 are present, progelatinase A activation is strongly inhibited. In contrast, TIMP-I is not efficient in preventing progelatinase A activation, as it is an extremely poor inhibitor of MTl-MMP (10). Since MTI-MMP seems to be activated intracellularly, the formation of TIMP-2 complexes and the activation of progelatinase A may occur intracellularly to some extent (R. Hembry & G. Murphy, unpublished results; 20).

ACTIVATION O F COLLAGENASE-3 BY MTl-MMP

Activation of procollagenase-3 in cellular model systems, such as Concanavalin A stimulated fibroblast monolayers or HT1080 cells transfected with wild type MTl-MMP, can be observed. Analysis of the activation products by Western blotting revealed that

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MURPHY el ol

this also involves a minimum of two sequential propeptide cleavage events, thereby confirming the data obtained in solution using purified MTl-MMP (4,6). Initial cleavage by MTl-MMP is observed at the

peptide bond within the propeptide domain, followed by a secondary cleavage event thereby releasing the rest of the propeptide domain (Tyr85 N- terminus; 4). The situation in these cellular model systems is complicated by the fact that the cells produce progelatinase A, which is activated by MTl- M M P In turn, active gelatinase A can activate procollagenase-3 (4). From inhibitor studies using the homologous TIMPs 1-3 it is clear that the initial cleavage event in this system is due to MTl-MMP. If gelatinase A were responsible for the activation of procollagenase-3, processing to the active form would be inhibited by TIMP-1, since this inhibitor has fast association rate constants for gelatinase A inhibition. TIMP-2 and TIMP-3 were efficient inhibitors of procollagenase-3 activation in line with their efficient inhibition of MT 1 -MMP Preliminary mechanistic studies to elucidate the functions of the different domains of procollagenase-3 in cellular activation revealed that processing is dependent on the presence of the C-terminal hemopexin-like domain. A C-terminal deletion mutant or a chimeric enzyme con- structed from N-terminal collagenase-3 and C-terminal MMP-19 (21) are not processed by cells expressing MTl-MMP (V. Knauper, A. M. Pendas, C. Lopez-Otin & G. Murphy, unpublished results). The mechanism of procollagenase-3 activation by cells expressing MT1-MMP shows the characteristics earlier demonstrated for progelatinase A processing in cellular model systems, but it is not at all clear whether this process also requires the presence of TIMP-2. Our current data using kinetic methods show that collagenase-3 does not interact with the C-terminal domain of free TIMP-2 (22) and thus the mechanism of procollagenase-3 activation by MT1-MMP may be profoundly different from that described above for progelatinase A activation by MTl-MMI?

THE INVOLVEMENT O F GELATINASE B IN MTl-MMP ACTIVATION CASCADES

It has been shown that co-ordinated activation of endogenous gelatinases A and B and collagenase-3 occurs when MTl-MMP is upregulated by treatment of SW 1353 chondrosarcoma cells with concanavalin A, in combination with IL-1B and oncostatin M (6; Fig. 2). In order to identify the role of collagenase-3 in the activation of progelatinase B cells were stimulated with phorbol myristate acetate, PMA. The induction of gelatinase B by PMA is comparable to that by IL-1B and oncostatin M, but induction of procollagenase-3 is much lower. Gelatinase A is

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A

+ + + ConA $- - TIMP-2

-t TIMP-1 - - kDa -

"- 0 +- activeCL-3

B - + + + ConA ~ - I - TIMP-2

kDa - + TIMP-1

Fig. 2. Concomitant activation of gelatinase A and B and collagenase 3 by chondrosarcoma cells. Effect of TIMPs. SW1353 cells were treated with IL-ID (10 ng/nil), on- costation M (50 ngiml) and concanavalin A, ConA (50 p g i ml) in DMEMiHam's F-12/0.2'%, LH for 3 days to induce synthesis of procollagenase 3 . TIMP-2 (3.3 pgiml) or TIMP- 1 (0.42 pgiml) were added with the IL-l and oncostatin M to examine the effect on proteinase activation. (A) Collagen- ase 3, CL-3. was assessed by Western blotting the con- ditioned media. Molecular mass standards are indicated on the left. (B) Gelatinases A and B. GLA. GLB: activation was assessed by zymography (shown as an inverted image).

constitutively expressed by these cells and most of these inducing agents have little effect on the overall production of this enzyme. Gelatinase A is activated by concanavalin A treatment of PMA stimulated cells, but in the absence of significant amounts of collagenase-3, gelatinase B is not activated. In other studies we have shown that activation of gelatinase B by collagenase-3 in vitro occurs at a rate dependent on the concentrations of the latent and the activating enzymes (5).

REGULATION OF THE SYNTHESIS AND ACTIVATION OF THE MT-MMPS

A number of reports of the regulation of MTI-MMP mRNA by cytokines have now been made. notably TNF-a upregulation in synovial cells and induction of mRNA by TNF-a. ILl-p, EGF and bFGF in human embryonic lung fibroblasts (23. 24). MTl-MMP expression in cultured chondrocytes was also shown


to be induced in the presence of the cytokines ILl-a and TNF-a. In chick embryo fibroblasts the mRNA levels for an MT-MMP (most closely related to MT3- MMP) were only modestly increased by bFGF or TNF-a and not affected by ILl-a or retinoic acid (25). The lectin Concanavalin A induces MT1-MMP activity in some cell types, including fibroblasts, and is generally accompanied by induction of progelatinase A activation (9, 24. 26, 27). In some cases Con- canavalin A mediates the up-regulation of MTI- MMP mRNA levels (9, 27) and in one study this was found to be effected in a c-Ras dependent manner (28). However, Concanavalin A could also be responsible for cross-linking of cell surface MTl-MMP, a form of "patching" or concentration of the enzyme, thereby facilitating rapid activation of progelatinase A. In some cell types treatment with phorbol esters can also modulate MTl-MMP and progelatinase A processing (24, 29). Recent studies have provided evidence that MTl-MMP synthesis is regulated by the cytoskeleton (30). Fibroblasts grown in a collagen gel produce low levels of MTI-MMP and synthesis is upregulated in relaxed lattices. This effect is mediated by the lack of stress fibres and treatment of fibroblasts with cytochalasin D, which disrupt stress fibres, leads to the initiation of increased MTl-MMP high mRNA levels and to progelatinase A activation (30. 3 I) . It has been noted that increasing intracellular calcium levels with ionomycin or thapsigargin inhibits Concanavalin A, TNF-a and phorbol ester induced progelatinase A activation (32). Yu et al. have shown that a calcium influx stimulated by ionomycin treatment of cells, blocks the processing of MTI - MMP and of progelatinase A without affecting the steady state mRNA levels (33). These data confirm that MTI-MMP processing is required for its function.

We have investigated the effects of extracellular matrix components such as fibronectin, tenascin and laminin-1 on gelatinase A activation by the MTl - MMP mediated mechanism (34). Fibronectin was found to upregulate gelatinase A activation in HT1080 cells, inducing a change in the levels of active enzyme comparable to that from treatment of the cells with phorbol myristate acetate. Laminin-1 and tenascin had no effect on gelatinase A. Fibronectin was only effective when cells were plated on to an adsorbed film and did not function in solution. To determine whether specific domains of fibronectin were involved we cultured HT1080 cells on polypep- tide fragments of fibronectin and found that the 120 kDa fragment was as effective as the full length molecule. HT1080 adhesion to fibronectin can be com- pletely inhibited by an antibody to the a5 integrin subunit (35). We found that HT1080 cells spread well on antibodies to the a5 subunit (monoclonal antibodies mAb 16 and mAb11). Adhesion to mAb16

promoted gelatinase A processing by the cells but mAb11 binding had no effect. Both antibodies are known to promote integrin receptor clustering, but only mAb16 mimics the effect of the fibronectin ligand (36). Fibronectin receptor occupancy would, therefore, appear to be important in the signalling mechanisms pertaining to the gelatinase A activation process. Interestingly, mAbl3 against the p l subunit of the a5bl integrin also promoted gelatinase A activation. Other reports have described the regulation of gelatinase A expression in response to integrin per- turbation, including a 2 and a3 in rhabdomyosarco- ma cells (37), a3 and a5 in glioblastoma cells and aVP3 and a6pl in melanoma cells (38). Clearly, increases in MMP2 expression and activation may be signalled by different integrin receptors, according to the cell type. In our studies on the fibronectin mediated modulation of gelatinase A activation by HT1080 cells we also showed that the levels of TIMP2 do not change and that MTl-MMP increases markedly at the protein, but not at the mRNA level. Levels of the 60 kDa active form of MTl-MMP were comparable in both unstimulated and fibronectin exposed cells but a 45 kDa breakdown product was sig- nificantly upregulated. Similar effects were observed on concanavalin A elicited activation of gelatinase A via MTl-MMP in skin fibroblasts or chondrosarcoma cells (Atkinson & Cowell, unpublished). Increases in the amount of the 45 kDa form of MTI-MMP corresponded to the extent of MMP2 activation but a direct link between the two phenomena remains to be established. Since the processed 45 kDa MT1- MMP remains membrane-associated it must be cleaved within the catalytic domain and rendered inactive, which could represent a significant regulatory event in MTl MMP function.

MTMMPs contain a basic sequence motif at the C-terminal end of the propeptide domain which is a potential recognition site for prohormone convertases, suggesting that these enzymes might be processed by subtilisin-related mammalian endoproteases. To date a number of proteases have been described which could be physiological activators of MT- MMPs, namely PC2, PC3/PC4, furin/PC, PC4, PC51 6 and 7/8 (3941). Thus MT-MMPs could potentially be processed within either the regulated or the consti- tutive secretory pathway. The first studies attempting to address this question demonstrated that MTl- MMP transmembrane deletion mutants were processed by co-expressed furin/PC (2 I), as had been demonstrated earlier for stromelysin-3 (42). This processing was inhibited by co-expression of a mutant a,-proteinase inhibitor (a,-Pittsburgh) which is known to inhibit furidPC (43,44). Furthermore, mu- tagenesis of the basic furidPC processing motif and expression of the mutant MT-MMPs in COS cells revealed that transmembrane domain deleted MT 1 -

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MURPHY (11 ( I / .

MMP was secreted into the culture medium as a proenzyme, thereby implicating furhiPC in intracellular processing of this soluble form of the enzyme. Inter- estingly, in the case of the expression of recombinant full-length membrane bound MTI -MMR co-expression of furidPC in COS cells had no effect on the molecular mass (63 kDa) of the membrane associated proteinase and it was suggested that the full-length enzyme might not be processed by furidPC (18). Furthermore. co-expression of a,-Pittsburgh had no effect on the activation of progelatinase A by membrane associated MTI -MMP in transfected COS cells, implying that the membrane bound MTI-MMP was fully functional and active. In addition. mutagen- esis of the furin/PC recognition site in the full-length MT1 -MMP molecule did not abrogate activation of progelatinase A. as would have been expected from the earlier studies using transmembrane deletion mutants. Thus furin/PC induced activation of membrane bound MTI-MMP did not appear to be a prerequi- site for progelatinase A activation. Recently, it was demonstrated that soluble proMT1-MMP can be activated by human plasmin in vitro by cleavage im- mediately downstream of Arg'OX and Arg"' in the basic furidPC recognition site (45). These results suggest that proMT1-MMP could be transported to the plasma membrane where the proenzyme is extra- cellularly activated by membrane associated plasmin. However, there is no evidence for plasmin activation of cell-associated MTI-MMP, in that the activation of progelatinase A by cell-bound MTI-MMP is not inhibited by addition of plasmin inhibitors in cellular activation experiments (Cowell, Knauper & Murphy, unpublished data). Since the amino terminal sequence of native active membrane bound MTI-MMP is Tyr"' , and this amino terminus was only partially generated by plasmin mediated cleavage of proMTl- MMP, suggesting that activation in vitro is unlikely to be mediated by plasmin. In conclusion. the physiological activator of membrane associated MT-MMP has not yet been discovered, but i t is clearly critical to the initiation of MMP activation cascades.

MT-MMPs AND CELL FUNCTION

It has previously been proposed that gelatinase A expression can promote cellular invasiveness in tumour cell models (46, 47). Hence particular attention has now been focused on a role for MT-MMPs in pro- moting cell invasion through the ECM. In their orig- inal paper Sat0 et al. (48) showed that overexpression of MTI-MMP in HTIOSO cells enhanced their rate of migration through a barrier of matrigel. Overex- pression of MTI-MMP in RPMI-7951 melanoma cells also increased the rate of degradation of fibronectin coated crosslinked gelatin films (46). The

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enzyme was localised predominantly on the surface of special membrane extensions, the invadopodia. which were the sites of matrix degradation. The transmembrane and cytoplasmic domains of MT 1 - MMP were required for the invadopodial localis- ation. Active gelatinase A was also shown to be partially localised on the invadopodia. providing specific spatially oriented foci of ECM degradation. Stable transfection of U2513 glioma cell lines with MTI- MMP showed an upregulation of endogenous progelatinase A activation (49). In a two-dimensional tumour spheroid outgrowth assay transfected cells showed enhanced migration on a collagen matrix. but decreased migration on vitronectin or fibronectin. The addition of TIMP-2 to the system prevented progelatinase A activation, decreased migration on collagen and enhanced migration on the other substrates.

The restriction of extracellular matrix proteolysis to the discrete pericellular environment involves complex mechanisms for the sequestration. activation and inhibition of degradative proteinases. The importance of the plasmin based M M P activation cascade relative to that based on MT-MMPs has yet to be determined, as well as the role of other proteinases such as the prohormone convertases. seprase and the newly emerging family of mammalian reprolysin and astacin homologues. The extracellular matrix itself may modulate the activity of these enzymes. Our understanding of these regulatory mechanisms in both development, repair and disease continues to grow and will undoubtedly lead to therapeutic targets for specific disease processes.

Work in our laboratory is supported by the Arthritis and Rheumatism Council, The Wellcome Trust, the Medical Re- search Council, U.K. and by the European Union.

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Mechanisms for pro matrix metalloproteinase activation

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