Báo cáo khoa học: Regulation of matrix metalloproteinase activity in health and disease pdf

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Báo cáo khoa học: Regulation of matrix metalloproteinase activity in health and disease pdf

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MINIREVIEW Regulation of matrix metalloproteinase activity in health and disease Elin Hadler-Olsen, Bodil Fadnes, Ingebrigt Sylte, Lars Uhlin-Hansen and Jan-Olof Winberg Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Norway Keywords activation; compartmentalization; complexes; exosite; heteromers; inhibition; matrix metalloproteinases Correspondence J.-O Winberg, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway Fax: +47 77 64 53 50 Tel: +47 77 64 54 88 E-mail: jan.o.winberg@uit.no (Received 30 April 2010, revised October 2010, accepted 18 October 2010) doi:10.1111/j.1742-4658.2010.07920.x The activity of matrix metalloproteinases (MMPs) is regulated at several levels, including enzyme activation, inhibition, complex formation and compartmentalization Regulation at the transcriptional level is also important, although this is not a subject of the present minireview Most MMPs are secreted and have their function in the extracellular environment This is also the case for the membrane-type MMPs (MT-MMPs) MMPs are also found inside cells, both in the nucleus, cytosol and organelles The role of intracellular located MMPs is still poorly understood, although recent studies have unraveled some of their functions The localization, activation and activity of MMPs are regulated by their interactions with other proteins, proteoglycan core proteins and ⁄ or their glycosaminoglycan chains, as well as other molecules Complexes formed between MMPs and various molecules may also include interactions with noncatalytic sites Such exosites are regions involved in substrate processing, localized outside the active site, and are potential binding sites of specific MMP inhibitors Knowledge about regulation of MMP activity is essential for understanding various physiological processes and pathogenesis of diseases, as well as for the development of new MMP targeting drugs Introduction Matrix metalloproteinases (MMPs) are a subfamily of zinc- and calcium-dependent enzymes belonging to the metzincin superfamily Characteristic for this superfamily is the HEXXHXXGXXH zinc-binding motif and a conserved methionine located C-terminal to the zinc-ligands, which forms a Met-turn [1] In humans, there are 24 MMP genes, but only 23 MMP proteins because MMP-23 is coded by two identical genes at chromosome MMPs are built up by various domains (Fig 1) All MMPs contain an N-terminal signal peptide that directs the enzymes to the secretory pathway, a prodomain with a conserved PRCGXPD sequence that confers the latency of the enzymes and a catalytic domain with the catalytic zinc localized in the large and relatively shallow active site cleft In addition, all MMPs except the two matrilysins (MMP-7 and -26) and MMP-23 contain a C-terminal hemopexin (HPX)-like domain that is linked to the catalytic domain through a hinge region In most MMPs, this hinge region consists of 10–30 amino acids, whereas, in MMP-9, this linker contains approximately 64 amino acids and is heavily O-glycosylated [2] In six of the membrane-anchored members of the MMP family, the HPX region ends in either a type I transmembrane domain with a short intracellular sequence or a glycosylphosphatidylinositol moiety MMP-23 differs from the Abbreviations APMA, p-aminophenylmercuric acetate; CS, chondroitin sulfate; FnII, fibronectin II; GAG, glycosaminoglycan; GSH, glutathione; Hp, haptoglobulin; HNL, human neutrophil lipocalin; HPX, hemopexin; MMP, matrix metalloproteinases; MMPI, metalloproteinase inhibitor; MT-MMP, membrane-type matrix metalloproteinase; NuMAP, nuclear MMP-3 associated protein; PG, proteoglycan; SIBLING, small integrinbinding ligand N-linked glycoprotein; TIMP, tissue inhibitor of metalloproteinase; TnI, troponin I 28 FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al Regulation of MMP activity Membrane-anchored MMPs Secreted MMPs N Propeptide domain Minimal domain Zn N Zn Catalytic domain MMP-7, -26 C Hinge-region Simple HPX domain N O-glycosylated hinge-region MMP-1, -3, -8, -10, -12, -13, -19, -20, -27 Zn HPX like domain MT4, -6-MMP FnII like module Furin-activated N RX[K/R]R motif MT1, -2, -3, -5-MMP MMP-11, -21, -28 Zn Zn N Cell membrane Fibronectin II-like domain N Zn N Zn MMP-2 Type I transmembrane domain N Type II transmembrane domain C Zn N Zn C MMP-23 GPI-membrane anchor C MMP-9 C N C-terminal Ca-Ig domain Fig Domain structure of secreted and membrane-anchored MMPs Most MMPs contain a propeptide domain, a catalytic domain, a linker (hinge-region) and a HPX domain The hinge region in MMP-9 is heavily O-glycosylated The three furin-activated MMPs and all of the membrane-anchored MMPs have a basic RX[K ⁄ R]R motif at the C-terminal end of their prodomains This motif can be cleaved inside the cells by furin-like proteinases The two gelatinases (MMP-2 and -9) contain three FnII-like repeats in their catalytic domain, N-terminal to the catalytic Zinc-binding site Four of the six MT-MMPs are anchored to the cell membranes through a type I transmembrane domain and the other two through a glycosylphosphatidylinositol moiety The seventh membrane-anchored MMP, MMP-23, has an N-terminal type II transmembrane domain The two minimal domain MMPs and MMP-23 lack the HPX domain and, in the latter enzyme, this domain is replaced by a C-terminal cystein array (Ca) and an immunoglobulin-like (Ig) domain other MMPs by lacking the HPX domain, which is replaced by a C-terminal cystein array region and an immunoglobulin G-like domain, and, instead of the N-terminal signal peptide, this enzyme contains an N-terminal type II transmembrane domain In two of the secreted MMPs, MMP-2 and MMP-9, the catalytic domain also contains a module of three fibronectin II (FnII)-like inserts A recent review described the molecular interactions of the HPX domains of the various human MMPs [3] The various domains, modules and motifs in the MMPs are involved in interactions with other molecules, and hence affect or determine the activity, substrate specificity, and cell and tissue localization, as well as activation, of MMPs Activation of proMMPs requires physical delocalization of the prodomain from the catalytic site, the so-called cystein-switch model [4] Two main mechanisms are involved in the activation of MMPs One is proteolytic cleavage and removal of the prodomain [5,6] and the other is allosteric activation where the prodomain is displaced from the catalytic site of the enzymes without being cleaved (Fig 2) Most of the MMPs are secreted as proenzymes and their activation occurs in the pericellular and extracellular space By contrast, all membrane-type (MT)-MMPs and three of the secreted MMPs contain a unique sequence (RX[K ⁄ R]R) at the C-terminal end of the prodomain (Fig 1) These MMPs can be activated intracellularly by furin, a serine proteinase belonging to the convertase family, which can cleave the prodomain at this unique sequence [5,6] Together, the MMPs are able to degrade most extracellular matrix (ECM) proteins In addition, they can process a large number of non-ECM proteins, such as growth factors, cytokines, chemokines, cell receptors, serine proteinase inhibitors and other MMPs, and thereby regulate the activity of these compounds as summarized recently [7] An increasing number of studies have shown that processing of some protein and peptide substrates by MMPs requires that the substrates not only interact with the active site, but also regions outside the active site Such regions are referred to as noncatalytic sites or exosites, which can be motifs localized in the catalytic domain or in one of the other domains An important role of the exosites may be to orient the substrate properly for cleavage and, for some substrates, exosite-binding is an absolute requirement for degradation A recent review [8] focused on current knowledge with respect to structural and functional bases for allosteric control of FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS 29 Regulation of MMP activity A E Hadler-Olsen et al Proteolytic cleavage of the pro- and HPX-domains SH N Zn Proteases Allosteric activation B N SH SH Zn N SH Zn Zn Mercurials 1a SH-reactive agents Chaotropic agents ROS N Detergents 1a HgCl2 / APMA Zn SH N Zn NGAL (HNL) SH Autocleavage 2a Zn Zn SH 2a Zn Autocleavage 3a Gelatin / Collagen IV / Collagen VI (α2chain) / SIBLING Autocleavage Zn SH SH Zn Zn Zn 3a Fig Proteolytic and allosteric activation of MMPs (A) Proteolytic cleavage of the pro- and HPX domain of MMPs by various proteinases, including serine proteases such as trypsin or other MMPs Steps 1–4 represents partly to fully processed propeptide, HPX and hinge regions Processing of the proMMP by another proteinase can be facilitated by the interaction of the target proMMP with other macromolecules that present the inactive proenzyme to its activator (not shown) Binding of mercurial compounds such as APMA or HgCl2, other SH reactive agents, reactive oxygen species (ROS), chaotropic agents and detergents such as SDS results in conformational changes of the proenzyme (step 1a) followed by activation through successive autocleavage of the propeptide (steps 2a and 3a) This may also be followed by autoprocessing of the HPX region (not shown) (B) Allosteric activation in which the propeptide remains intact (step 1), as suggested for the binding of proMMP-9 to gelatin or collagen IV, binding of proMMP-2 to collagen VI (a2 chain), as well as binding of individual SIBLINGS to specific MMPs (see text) Binding of HgCl2 or APMA to proMMP-9 results in a conformational change (step 1a) followed by autocleavage that did not remove the conserved PRCGV sequence from the enzyme (step 2a) This truncated enzyme had a low specific activity Neutrophil gelatinase associated lipocalin (NGAL) ⁄ human neutrophil lipocalin (HNL) bound to the new N-terminus without further processing of the enzyme (step 3a), resulting in a fully active enzyme (see text) MMP activities Previous reviews have described new techniques that can be used in the search for exosites and examples of exosites derived from the use of these techniques [9,10] Although our knowledge of specific exosites in the various MMPs is still very limited, these sites will become of increasing importance as targets for future drug development Hopefully, future drugs will not affect all substrate degradation by a given enzyme, but only the processing of selected substrates Some of the substrates that MMPs are known to process are localized intracellularly [7] Although all MMPs contain a signal peptide that directs them to the secretory pathway, an increasing number of reports have found various MMPs localized also inside cells This may partly explain the ability of some MMPs to process intracellular proteins and further demonstrates the complex roles of MMPs under physiological and pathological conditions Among the earliest intracellular MMP substrates detected are troponin I (TnI) [11], aB-crystallin [12] and lens bB1 crystallin [13] In vivo, MMP cleavage of these substrates was linked to health 30 and disease MMP-2 degradation of TnI is associated with diminished contractive function of the heart [11], MMP-9 degradation of aB-crystallin with multiple sclerosis [12] and MMP-9 cleavage of lens bB1 crystallin with cataract [13] MMPs interact with various cell surface and pericellular molecules that alter the function of the enzyme, as well as affect cellular behaviour [14] MMP-induced cleavage and degradation of ECM and non-ECM molecules may either prevent or provoke diseases such as cancer [15], as well as cardiovascular, autoimmune, neurodegenerative and various connective tissue diseases Knowledge about the regulation of MMP activity is therefore important for understanding various physiological processes, as well as the pathogenesis of a large number of diseases In addition, such knowledge is also important for the development of novel treatment strategies A number of excellent reviews on MMPs and their functions are available The present review focuses on the regulation of MMP activity with an emphasis on post-translational modifications, the FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al formation of heterodimers and complexes, compartmentalization, and the role of exosites in substrate degradation and enzyme inhibition Activation mechanisms To induce activation of a proMMP, the prodomain must be physically delocalized from the catalytic site (Fig 2) There are various ways to achieve such a delocalization followed by activation One is through S-reactive agents, organomercurials and reactive oxygen species, interacting with the conserved cysteine in the prodomain Another is the induction of conformational changes through binding of chaotropic agents and detergents such as SDS In all cases, the conformational changes (Fig 2A, step 1a) are followed by an autocatalytic stepwise degradation of the prodomain (Fig 2A, steps 2a and 3a) [5,6] Proteinases can cleave the prodomain in one or several steps, producing an active MMP with reduced molecular size A large number of proteinases such as serine and metalloproteinases are involved in the activation of proMMPs In some cases, one enzyme generate a partly active enzyme that can be fully activated by a second enzyme removing one or more amino acids from the prodomain, as described for MMP-1 [5,6] Thus, it is not sufficient to remove the zinc-binding motif in the prodomain of the MMP to obtain a fully active enzyme; the catalytic efficiency of the activated MMP also depends on the cleavage site C-terminal to this motif Both MMP-2 and MMP-9 have been shown to be activated in vivo by serine proteinases such as chymase and trypsin, suggesting a biological relevance Using knockout mice, it was also shown that mast cell chymase had a key role in the activation of proMMP-9 and proMMP-2 [16] In mice with acute pancreatitis, trypsin induced the activation of proMMP-2 and proMMP-9 ProMMP-9, when activated by endogenous trypsin, was reported to be a permissive factor for insulin degradation and diabetes [17] Similarly, a significant association between high endogen concentrations of trypsin and activation of proMMP-9 was found in ovarian tumor cyst fluids [18] Trypsin has been shown to be an efficient activator of most proMMPs in vitro [6] Instead of activating proMMP-2, it was reported that trypsin induced degradation of the enzyme [19] Other studies showed that trypsin could activate proMMP-2, although less efficiently compared to compounds such as p-aminophenylmercuric acetate (APMA) [20–23] There is no contradiction in these results We have shown that the balance between activation and degradation is dependent on the activation- Regulation of MMP activity temperature as well as trypsin concentration and the two additives, Brij-35 and Ca2+ [22] At 37 °C, the presence of 0.05% Brij-35 and 10 mm Ca2+ mainly prevented both activation and degradation, whereas a lack of these two compounds resulted in trypsininduced degradation However, at intermediate concentrations of Brij-35 and Ca2+, trypsin induced the activation of proMMP-2 Different modes of activation can have implications for the biochemical properties of the enzymes depending on the cleavage site In the trypsin-activated MMP-2, the N-terminal residue was either Lys87 or Trp90 [22], with the former being identical to the cleavage site generated by human trypsin-2 [23] The N-terminal residue was Tyr81 in membrane-type1 MMP (MT1-MMP) or APMA-activated enzyme [6] The slightly shorter N-terminus in the trypsin-activated enzyme resulted in reduced catalytic efficiency and weaker tissue inhibitor of metalloproteinase (TIMP)-1-binding compared to the enzyme activated by MT1-MMP or APMA [22] Docking studies of TIMP-1 revealed that the slightly weaker binding of the inhibitor to the trypsin-activated MMP-2 could be attributed to its shorter N-terminus (Lys87 ⁄ Trp90 versus Tyr81) because Phe83 and Arg86 interacted directly with the inhibitor Activation through domain specific interactions A proMMP can be presented to its activator proteinase by interactions with other proteins or glycosaminoglycans (GAGs) In addition, interactions between a proMMP and other molecules can result in an active MMP without proteolytic processing of the propeptide, allosteric activation (Fig 2B) It is sufficient that the propeptide is distorted away from the active site, which leaves an open active site that can bind and process substrates Removal of the binding partner causes a reversion into an inactive proenzyme Below, we review some of the recent literature that has focused on the role of various proMMP-binding partners involved in activation Allosteric activation Gelatinase interactions with collagen and gelatin Binding of macromolecules or specific thiol-binding reagents to an MMP with an intact or a partially cleaved prodomain can induce enzyme activation despite the presence of the conserved PRCGXPD sequence ProMMP-9 bound to either a gelatin or type IV collagen-coated surface could cleave a fluorogenic peptide substrate, as well as gelatin, even if the FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS 31 Regulation of MMP activity E Hadler-Olsen et al prodomain of the enzyme remained intact [24] The specific activity of the proenzyme bound to the gelatincoated surface was approximately 10% of the active MMP-9 bound to the same surface Furthermore, the enzymatic activity of both enzyme forms was inhibited by TIMP-1 with comparable kinetics Similar observations were made for proMMP-2 The proenzyme could degrade DQ-gelatin in the presence of low concentrations of the triple-helical domain of the a2 chain of the microfilamentous collagen VI [25] The above examples are illustrated in Fig 2B (step 1) Interactions with small integrin-binding ligand N-linked glycoprotein (SIBLING) Individual members of the SIBLING family are known to bind strongly to both pro- and active forms of specific MMPs Bone sialoprotein binds MMP-2, osteopontin binds MMP-3 and dentin matrix protein-1 binds MMP-9, all with a : stoichiometric ratio and binding constants in the nanomolar range [26] These SIBLINGs and MMPs are also co-expressed and colocalized in salivary glands of humans and mice [27] The interaction between the SIBLING and its partner proMMP resulted in an active MMP without autocatalytic removal of the propeptide [26] Studies indicated that binding of a SIBLING to a proMMP induced large conformational changes in the enzyme, suggesting that the propeptide is physically removed from the catalytic site, thereby allow substrate binding (Fig 2B, step 1) Furthermore, the three SIBLINGs have a tento 100-fold higher affinity for the complement regulator factor H than for their partner MMPs The proMMP ⁄ SIBLING complex was dissociated in the presence of factor H and a re-inactivation of the catalytic activity by the still attached propeptide [26] The same research group also showed that the amino-terminal region, especially exon 4, is essential for bone sialoprotein-mediated activation of proMMP-2 [28] It appears that bone sialoprotein also can regulate the activity of active MMP-2 by modulating the inhibitory effect of TIMP-2 and synthetic MMP-inhibitors [28,29] The findings of a recent study challenged the view that certain SIBLINGs are able to bind and induce allosteric activation of specific MMPs [30] Interactions between proMMP-9 and neutrophil gelatinase associated lipocalin Human neutrophil lipocalin (HNL), also called neutrophil gelatinase associated lipocalin, is known to form a strong reduction sensitive heterodimer with proMMP-9 [31,32] Mercurial compounds such as APMA and 32 HgCl2 are known to partly activate the 92 kDa proMMP-9 in several constitutive steps that generate an 83 kDa form of the enzyme with the M75RTPRCGV peptide as the N-terminal sequence [6] Hence, the conserved Cys80 that interacts with the catalytic zinc is not removed (Fig 2B, steps 1a and 2a) Treatment of proMMP-9 with an excess of HNL also induced a partial activation of the proenzyme with an identical N-terminus as the HgCl2 exposed enzyme [33] When the enzyme was activated with a combination of HgCl2 and HNL, this resulted in a fully active enzyme with an activity comparable to trypsin activated MMP-9 [33] Despite the full activity of the HgCl2 and HNL activated enzyme, this had an N-terminus identical to the HgCl2 activated enzyme (Fig 2B, step 3a) [33], whereas trypsin activation of MMP-9 caused removal of the entire propeptide, with Phe88 as the N-terminal residue (Fig 2A, steps and 2) [6] Similar results were obtained with isolated proMMP-9 homodimer and proMMP-9 ⁄ HNL heterodimer when activated with HgCl2 and an excess of HNL By contrast, HNL had no effect on trypsin-activated MMP-9 Kallikrein is a plasma proteinase that can partially activate proMMP9, and the presence of an excess of HNL resulted in a synergistic effect with a 30–50% increase in activity compared to kallikrein activation alone Altogether, this suggested that the N-terminus of the partially activated proenzyme is entrapped in the hydrophobicbinding pocket of HNL and the propeptide–HNL complex is thereby detached from the catalytic site, generating a fully active enzyme without further truncation (Fig 2B, step 3a) [33] Activation by peroxynitrite and glutathione Enzymatic activity of intact proMMPs against physiological substrates has also been detected in the presence of peroxynitrite and glutathione (GSH) [34] Examples of this are proMMP-1 and -8 processing of triple helical collagen I, and proMMP-9 processing of gelatin One of the products generated when GSH reacts with peroxynitrite is GSNO2 It was shown that this product most likely activates the proenzymes through S-glutathiolation of the cystein in the conserved PRCGXPD sequence of the propeptide by forming a stable disulfide S-oxide [34] Peroxynitrite can also induce activation of proMMP-2 without loss of the prodomain This activation appeared to be concentration-dependent and was attenuated by GSH [35] Other studies have reported activation of proMMP-2 by peroxynitrite, although the activation was followed by a cleavage of the enzymes prodomain, resulting in an enzyme with a reduced molecular size [36,37] Thus, FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al peroxynitrite as well as GSH along with peroxynitrite may activate the MMPs by two completely different mechanisms: one being allosteric and the other comprising an autocatalytic removal of the prodomain Peroxynitrite has also been shown to inactivate TIMP-1 [38] Thus, it appears that peroxynitrite potentiates MMP activity not only by the direct activation of proMMPs, but also by preservation of MMP activity after it is generated There appear to be a controversy whether GSNO is able to directly induce activation of MMPs by modulating the conserved Cys in the enzyme prodomains [39] Activation through proteolytic removal of the prodomain TIMP regulation of MT1-MMP-induced activation of proMMP-2 MT1-MMP-induced activation of proMMP-2 is a twostep process involving the MMP inhibitor, TIMP-2, which has been described in detail in several reviews Briefly, it has been shown that the TIMP-2 enhancement of the MT1-MMP-induced activation of proMMP-2 is a result of the formation of a ternary complex where the inhibitor acts as a link between the two enzymes In this complex, the MT1-MMP is inactive as a result of its interaction with the N-terminal part of TIMP-2, whereas the C-terminal part of the inhibitor binds to the HPX domain of proMMP-2 Another MT1-MMP molecule can now cleave the proMMP-2 in the complex and generate a 64 kDa inactive intermediate This intermediate is further autocatalytically processed into the fully active 62 kDa form of MMP-2 [40,41] The step at which TIMP-2 is involved when it enhances the MT1-MMP-induced activation of proMMP-2 has been questioned because studies have shown that the inhibitor enhances the autoactivation step, but is not necessary for the first cleavage step [42–44] The other TIMPs, TIMP-1, -3 and -4, can also regulate the MT1MMP-induced activation of proMMP-2 [43], where TIMP-1 only prevents the second step (autoactivation) and locks the enzyme in an inactive intermediate form [43,45] These examples demonstrate the complexity of the MT1-MMP-induced activation of proMMP-2 and how the activation process can be differently regulated by various TIMPs MT-MMP-induced activation of proMMP-2 Other MT-MMPs can also activate proMMP-2, although this activation does not involve TIMP-2 Both the MT2-MMP and the MT3-MMP-induced Regulation of MMP activity activation of proMMP-2 required a proMMP-2 with an intact HPX domain [46,47] Both MT3-MMP and proMMP-2 bind to chondroitin sulfate (CS) chains of cell surface proteoglycans (PGs) This interaction enhances the activation of proMMP-2, probably by presenting the gelatinase to its membrane-bound activator [46] Both the catalytic and the hinge region of the MT3-MMP interacted with the CS-chains, whereas proMMP-2 interacted through the HPX domain Furthermore, CS-chains with the sulfate attached to the 4-position of the GAG-chains (C4S) but not to the 6-position (C6S) enhanced the activation in the presence of suboptimal concentrations of MT3-MMP Binding of proMMP-2 to the CS-chains without MT3-MMP did not result in activation The complex interactions of various proteins involved in MT-MMPinduced activation of proMMP-2 are further elucidated by the involvement of claudins, which are tetraspan membrane proteins MT-MMP mediated proMMP-2 activation was enhanced in the presence of claudin-1, -2, -3 and -5 [48] Claudins not only replaced TIMP-2 in the MT1-MMP-induced activation of proMMP-2, but also enhanced the activation of proMMP-2 by all MT-MMPs Claudin-1 binds to both MT1-MMP and proMMP-2, and this binding appears to involve only the catalytic domains of the two enzymes Another membrane protein shown to enhance MT1-MMPinduced activation of proMMP-2 was avb3 integrin [49–51] MMP-2 binds through its HPX domain to an MT1-MMP-cleaved and activated form of avb3 integrin [49–52] This activated integrin enhanced the second autocatalytic step of the activation by binding to the 64 kDa intermediate form of MMP-2 [52] Binding and activation of MMP-2 was abrogated in the presence of avb3 integrin-binding macromolecules such as vitronectin and HKa (two-chain high molecular weight kinogen) [50,52,53] Binding of MMP-2 to avb3 integrin appears to be controversial because the findings of another study did not support an interaction between MMP-2 ⁄ PEX and avb3 integrin [54] Activation through interactions with elastin, heparin and CD151 ProMMP-2 and active MMP-2 binds to soluble and insoluble elastin through the FnII module of the catalytic domain [55] When proMMP-2 binds to insoluble elastin, this induces a fast autoactivation of the proenzyme followed by inactivation [56] A similar phenomenon of enhanced autolysis has also been observed when proMMP-2 binds to heparin, although this binding involves the enzymes C-terminal HPX domain [57] These are just two examples of how an interaction of FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS 33 Regulation of MMP activity E Hadler-Olsen et al the proenzyme with various ECM components regulates the activity of the enzyme One of the two minimal domain MMPs, proMMP-7, can also be captured and activated at cell membranes The proMMP-7 propeptide can interact with the C-terminal extracellular loop of the transmembrane protein CD151 [58] The interaction between the propeptide and CD151 was suggested to induce conformational changes followed by autocatalytic activation Formation of proMMP-9 dimers affect activation of the enzyme MMP-9 is known to form various types of dimers including homo- and heterodimers that involve the C-terminal HPX-like domain of the enzyme [31,59–63] The proMMP-9 monomer is more rapidly activated by MMP-3 than the homodimer [61] The interaction between the C-terminal domain of proMMP-9 and a CSPG core protein has also been shown to affect the activation of proMMP-9 [64] By contrast to the proMMP-9 monomer and homodimer, the proMMP9 ⁄ CSPG complex was not activated by the organomercurial compound APMA [64] On the other hand, Ca2+ which is known to stabilize but not activate MMPs, induced a concentration independent and hence intramolecular autoactivation of the proMMP-9 bound to the CSPG The Ca2+-induced activation resulted in a proteolytic removal of the propeptide from the complex bound proMMP-9 In the presence of Ca2+, activated enzyme forms were also released from the complex This was the result of cleavage of a part of the PG core protein and at least a part of the C-terminal HPX domain of proMMP-9, leaving the hinge region bound to the enzyme [64] A large reduction of the HPX is likely to alter substrate specificity because several specific substrate exosites in the HPX domain may have been removed Only the proMMP-9 in the CSPG complex was activated when Ca2+ was added to a mixture of purified proMMP-9 and proMMP-9 ⁄ CSPG complex Furthermore, a mixture of Ca2+ and APMA did not activate the proMMP9 ⁄ CSPG complex [64], although Ca2+ is known to participate and enhance APMA induced activation of proMMP-9 [62,65–67] During hemolysis and ⁄ or hemorrhage, Hb is released into the circulation and ⁄ or into surrounding tissues Heme, the prostetic group of Hb, is released from the protein and converted to hemin, the Fe3+ oxidation product of heme During malaria infection, Hb inside the red blood cells is digested by parasites This results in the production of the chemically inert crystalline substance, hemozoin, which is released into the circulation 34 when the red blood cells burst Hemozoin is indentical to b-hematin, the synthetic form of hemozoin The HPX domain of proMMP-9 can bind to both hemin and b-hematin, which results in an autocatalytic truncation of parts of the enzyme’s prodomain [68] The truncation in the presence of hemin results in two enzyme forms with Arg17 and Thr64 as N-terminal residues b-hematin induced truncation results in two enzyme forms with Arg42 and Leu54 as new N-terminal residues, with the former identical with the first cleavage by MMP-1,-2,-3,-7 and -13 [6] These partly truncated forms of MMP-9 are inactive The presence of the hinge region of the enzyme accelerated the truncation process b-hematin, but not hemin, accelerated MMP-3 induced activation to the fully active 82 kDa MMP-9 with Gln89 as N-terminal Activity regulated through the formation of heterodimers and complexes Some of the dimers formed with MMP-9 are detected in SDS ⁄ PAGE under nonreducing conditions, but not under reducing conditions Hence, these dimers are reduction sensitive and assumed to be linked through one or several disulphide bridges The formation of different MMP-9 complexes results in altered biochemical properties of the enzyme In cells that produce both proMMP-9 and TIMP-1, these two molecules are bound together through their C-terminal domains, and the presence of TIMP-1 affects the activity of the enzyme [69] When proMMP-9 forms a dimer with collagenase, binding to TIMP-1 is prevented [70] There are conflicting data concerning whether the proMMP-9 homodimer is able to form a complex with TIMP-1 [59,61,71] In its heterodimer form with neutrophil gelatinase associated lipocalin, proMMP-9 can bind TIMP-1 and form a ternary complex [72] and the enzyme is protected from degradation [73] Two members of the cystatin family, fetuin-A and cystatin C, bind to MMP-9 and protect the enzyme from autolytic degradation [74] The above examples show that there are different ways by which the activity of an MMP can be regulated and preserved Both MMP-9 and MMP-2 interact with gelatin as well as collagen through the three FnII-like modules in their catalytic domain [70,75–84] This interaction is important for the ability of these enzymes to degrade these physiological substrates, although it has no effect on their degradation of several other physiological substrates or chromogenic peptide substrates ProMMP-9 forms a complex with one or several CSPG core FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al proteins through its HPX domain [64] When proMMP-9 is bound to CSPG core proteins, the enzyme cannot bind gelatin, suggesting that the gelatin-binding sites in the FnII-like modules of the enzyme are masked [85] Complex formation involving more than one domain in the enzyme is likely a result of the high structural flexibility of the large hinge region The extreme flexibility of MMP-9 was demonstrated by atomic force microscopy combined with small-angle X-ray scattering and analytical ultracentrifugation [86] The interaction between proMMP-9 and CSPG core proteins has resulted in changes of several biochemical properties of the enzyme On this basis, it is tempting to assume that active MMP-9 still attached to the CSPG core protein will have altered biochemical properties compared to unbound active MMP-9 Such properties may include substrate specificity, catalytic efficiency and ability to interact with inhibitor molecules, hence giving rise to altered regulation of enzyme activity Haptoglobulin (Hp) is a plasma protein mainly expressed in the liver, and belongs to the family of acute-phase proteins that is induced during the inflammatory process Hp consists of a dimer of ab-chains covalently linked by disulphide bonds, as well as oligomers [87] Hp have a high affinity for Hb (Kd = 10)12 m), and is considered to be involved in the clearance of Hb The HPX region of MMP-9 has been shown to form a strong reduction sensitive complex with Hp [88] Gelatin was reported to bind more strongly to the proMMP-9 ⁄ Hp complex than to either proMMP-9 monomer or homodimer, although the specific activity against gelatin was similar for the active MMP-9 ⁄ Hp complex and the active MMP-9 monomer Furthermore, binding of proMMP-9 to Hp did not influence the activation of the enzyme by MMP-3 Binding of MMP-9 to Hp may comprise a method of regulating MMP-9 activity because Hp is known to bind cellular receptors followed by internalization and degradation Role of exosites in regulation of activity The complex substrate specificity of individual MMPs is not only determined by their substrate-binding subsites on each side of the catalytic zinc, but also by substrate-binding to motifs outside this region (exosites) The role of exosites has been recognized for a long time for enzymes acting on polymer biomolecules such as the restriction endonucleases [89], although was not reported until 1989 for MMPs [90] It was observed that stored MMP-1 was autocatalytically truncated, which resulted in a processed enzyme lacking the Regulation of MMP activity C-terminal HPX domain This truncated enzyme was no longer able to cleave triple helical collagen I, but was able to degrade gelatin (denatured collagen) The HPX region was also found to be necessary for the cleavage of the triple helical region in interstitial collagen by other collagen-degrading MMPs (MMP-2, -8, -13 and 14) [91–95] The active site region in the MMPs is too ˚ ˚ narrow (5 A) to allow a triple helical collagen (15 A) to enter the active site The HPX region in the collagenases locally unwinds the triple helical collagen, and then a single a-chain can enter the catalytic site and be cleaved [96] In addition, it was shown that a small segment in the catalytic domain, R183WTNNFREY191, is necessary for the enzymes ability to cleave triple helical collagen [96] Production of MMP-3 ⁄ MMP-1 chimeras revealed that additional unique structural elements in the catalytic domain are involved In the two gelatinases, MMP-2 and MMP-9, the FnII-like repeats in the catalytic site of the enzymes can interact with elastin, type I, III, IV, V, X and XI collagens, as well as gelatins This may facilitate the localization of these enzymes to connective tissue matrices This interaction appears to be of importance for the degradation of macromolecules such as elastin, gelatin and collagens IV, V and XI, but does not influence the degradation of chromogenic substrates or other macromolecules [70,75–84] Hence, the FnII-like module in the gelatinases contains important exosites for the degradation of some substrates Many potent small molecule MMP inhibitors (MMPIs) have been entered into clinical trials for cancer treatment, although most of them have been discontinued as a result of a lack of specificity and selectivity Successful cancer therapy based on MMPIs must not only be selective against MMPs validated as targets, but also spare MMPs validated as antitargets [97,98] To develop new therapeutic MMPIs, it is of pivotal importance to understand the structural basis of recognition, binding and cleavage of substrates, as well as the recognition and binding of natural inhibitors (TIMPs) Recent data indicate that subtype specific inhibitors may also lead to new treatment of acute and chronic inflammatory and vascular diseases [99] Most known MMPIs are targeting the catalytic region and the catalytic zinc, which are very similar between the MMPs Designing specific small molecular MMPIs targeting the catalytic site is therefore problematic [99] MMPIs targeting less conserved binding sites outside the prime subsites of MMPs are considered to be more specific Within the MMP family, distinct preferences for collagen types are seen, which must reflect structural differences in MMP collagenbinding [100] Exosites are considered to be important FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS 35 Regulation of MMP activity E Hadler-Olsen et al determinants for these differences in specificity by introducing contact regions between the substrate and the MMP outside the primary specificity subsites Exosites are regarded as novel binding sites that represent unique opportunities for designing subtype selective inhibitors Efforts have been put into both high throughput screening [101] and the design of inhibitors targeting exosites without interfering with the catalytic zinc [8] Such inhibitors are considered to act selectively against the degradation of a specific substrate, and represent a novel therapeutic approach with putative reduced side effects Binding of the collagen triple helix is necessary for collagenolysis Some studies have taken advantage of potential substrate exosites in MMP-2 and MMP-9 collagenolytic behaviour by designing triple helical substrate and triple helical transition state analogues One such study indentified inhibitors with high selectivity for the gelatinases (MMP2- and MMP-9) compared to other MMPs [102] Furthermore, the FnII insert of MMP-9 was suggested to contain exosites involved in the binding of type V collagen model substrates and inhibitors A triple helical peptide that incorporates an FnII insert-binding sequence was constructed and found to give selective inhibition of MMP-9 type V collagen-based activity [103] Exosites related to collagenolysis have also been identified in the active site cleft [104] and the catalytic domain [105] of MMP-1, and were also suggested in analogous regions of MMP-8 and MMP-13 [106] Recently, a highly selective MMP-13 inhibitor was reported that did not chelate the catalytic zinc, but instead bound in the S1¢ pocket [107] This structural region shows diversity among MMPs A recent study has further elucidated the role of the specificity loop for selective MMP-13 inhibition by indentifying the steric requirements for binding to this region [108] Other studies have also described selective MMP-13 inhibitors that not interfere with the catalytic zinc [101,109] Regulation of activity through compartmentalization Through their motifs and modules, the secreted MMPs are directed to various compartments in the extracellular environment as well as to cell membranes Among their binding partners in these compartments are collagens, laminins, fibronectin, elastin, core proteins and GAG-chains of PGs This compartmentalization regulates the MMP activity by locating and concentrating them close to or on potential substrates The interaction with their binding partners varies in strength, which has implications for the ability to extract a given 36 enzyme from a tissue Examples are the binding of MMP-1, -2, -7, -8, -9 and -13 to heparin and heparan sulfate [57,72,110–117], where the interaction with heparin occurs through the HPX domain of MMP-1, -2 and [110,112,116] MMP-7 lacks the HPX domain and interacts through the catalytic and the prodomain This MMP binds much stronger to the GAG-chains than the other MMPs [117] MMP-7 could be extracted from tissues by heparinase digestion or by using extraction buffer containing heparin, heparan sulfate or protamin [117] Similarily, it was necessary to use various extraction conditions to quantify the amount of gelatinases in mouse kidneys [118] Binding of secreted MMPs to cell membranes is another way of regulating their activity This may lead to the activation of the enzymes, as discussed above, and promote cell migration and cell invasion through basement membranes and tissues Binding of MMPs to cell membranes may also activate intracellular signaling cascades, an effect independent of their proteolytic activities [119–123] Cell surface associated enzymes can also be internalized and either directed to the lysozymes for destruction or be a source of intracellular activity An emerging concept in MMP regulation is their intra ⁄ extracellular location because both secreted and membrane bound MMPs have been found localized to various intracellular sites In the following part of present minireview, we focus on the subcellular location, processing of intracellular substrates and putative physiological relevance of this activity Nuclear localization MMP-2, -3, -9, -13 and MT1-MMP have been demonstrated in the nucleus of various cell types, including heart myocytes, brain neurons, endothelial cells, fibroblast and hepatocytes The mechanisms of nuclear translocation of the different MMPs are generally poorly characterized MMP-2 has a typical nuclear localization sequence close to the C-terminus that might be involved in the nuclear localization [124] A nuclear signaling sequence is also found in the catalytic domain of MMP-3, which appeared to be essential for the translocation to the nucleus Full-length MMP-3 was absent from the nucleus, suggesting that processing is required to expose the nuclear localization signal for nuclear transport [125] For MT1MMP, a caveolae-mediated endocytosis has been suggested as a mechanism of internalization and nuclear translocation as a result of the colocalization of caveolin-1 and MT1-MMP in perinuclear regions [126] Nuclear localization of MMPs has been associated with apoptosis in several studies Increased nuclear FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al gelatinolytic activity, colocalized with MMP-2, has been demonstrated in pulmonary endothelial cells undergoing apoptosis MMP-2 activation in these cells was suggested to be induced by reactive oxygen and nitrogen species produced by cigarette smoke [127] Intranuclear gelatinolytic activity has also been observed in rat brain neurons after post-ischemic reperfusion, and this activity was associated with DNA fragmentation Furthermore, this gelatinolytic activity colocalized with MMP-2 and MMP-9, and was reported to be markedly reduced in the presence of a general MMP inhibitor or by MMP-2 and MMP-9 antibodies MT1MMP as well as furin, a MT1-MMP activator, was also found in the nucleus of the ischemic rat brain neurons, suggesting a possible mechanism for intracellular activation of MMP-2 by MT1-MMP [128] In both cardiac myocytes and pulmonary endothelial cells, as well as in brain neuronal cells, nuclear gelatinolytic activity is correlated with the processing of two important factors in the DNA repair machinery (i.e the DNA repair enzyme poly-ADP-ribose polymerase and X-ray cross-complementary factor 1, which protect cells from apoptosis) These two factors were shown to be processed by MMP-2 and MMP-9 [124,128] Thus, nuclear MMP activity may contribute to the apoptotic process after ischemic injuries by processing polyADP-ribose polymerase and X-ray cross-complementary factor and hence interfere with the oxidative DNA repair system [128] In addition to MMP-2 and MMP-9, expression of active MMP-13 was also increased in the nucleus of neural cells after cerebral ischemia in both rats and humans The nuclear translocation of MMP-13 was promoted by oxygen and glucose deprivation in the cells following ischemia, although the biological relevance of this is not known [129] Active MMP-3 in the nuclei of chondrocytic cells in culture and in nuclei of normal and osteoarthritic chondrocytes in vivo has been shown to be involved in transcriptional gene regulation [130] Nuclear MMP-3 bound to a transcription enhancer sequence (TRENDIC) in the connective tissue growth factor (CCN2 ⁄ CTGF) promoter and activated transcription of CCN2 ⁄ CTGF This growth factor promotes physiological chondrocytic proliferation and ECM formation Pro- and active MMP-3 could activate the CCN2 ⁄ CTGF promoter, where various domains of the MMP participated in the activation Both the HPX and the Cat-Hinge regions activated the promoter, whereas the prodomain and the hinge-region alone had no effect on the activation Compared to the wildtype MMP-3, lower promoter activation occurred in the presence of catalytically dead MMP-3 mutants Regulation of MMP activity This suggested that MMP-3 can regulate the CCN2 ⁄ CTGF promoter activity by two completely different mechanisms One involves proteolytic processing of one or several nuclear proteins, whereas the other is independent of the processing capacity of the proteinase and involves the HPX domain A DNA-binding domain was found in the HPX domain, as an antiMMP-3 HPX antibody blocked the protein-DNA interactions The hinge region contains proline-rich sequences found in some transcription factors The properties of MMP-3 as a transcription factor was evaluated by analyzing nuclear MMP-3 associated proteins (NuMAPs) Several NuMAPs were detected, such as heterochromatin proteins, transcription co-activators ⁄ corepressors, RNA polymerase II and nucleosome ⁄ chromatin assembly protein One of the NuMAPs, HP1c, was demonstrated to interact with MMP-3 and to co-activate the CCN2 ⁄ CTGF promoter with MMP-3 Another identified NuMAP was the transcription repressor NCoR1, suggesting that MMP-3 might degrade NCoR1 to prevent transcription repression of the CCN2 ⁄ CTGF promoter [130] Cytosolic and vesicle localization A study on dopaminergic neurons suggested a proapoptotic role of active intracellular MMP-3 During apoptosis, the proform of MMP-3 was cleaved to a catalytically active form (48 kDa) by a serine proteinase [131] Lack of intracellular MMP-3 activity protected the dopaminergic cells from apoptosis Inhibition of the MMP-3 activity attenuated the activation of caspase-3, the executioner enzyme in apoptosis By contrast to the apoptosis-promoting effects of cytosolic MMP-3 and the MMPs localized in the nucleus, perinuclear MMP-1 appeared to prevent apoptosis [132] Intracellular MMP-1 has been demonstrated in various cell types, including glia cells, epithelial cells and fibroblasts At an early state of apoptosis, both the pro- (57 kDa) and the active (45 kDa) forms of MMP-1 colocalized with mitochondria that clustered around the nucleus At later stages, it accumulated around the nucleus and nuclear fragments, suggesting a possible role in the breakdown of the nuclear envelope Furthermore, the intracellular levels of MMP-1 varied with cell cycle progression and were highest during the M phase These observations suggest that intracellular association of MMP-1 to mitochondria and nuclei have implications for the control of cell growth, and may contribute to the well-known association of this enzyme with tumor cell survival and spreading [133,134] FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS 37 Regulation of MMP activity E Hadler-Olsen et al Intracellular MMP-2 activity has been shown to be a mediator of acute myocardial (ischemia ⁄ reperfusion) stunning injuries, characterized by a reversible loss of contractile function during the post-ischemic reperfusion phase [11] In vitro and in vivo studies suggested that this was a result of MMP cleavage of the contractile protein regulatory element, TnI, and the cytoskeletal protein a-actinin [11,135,136] Other possible MMP-2 substrates in cardiac myocytes are desmin and myosin light chain-1 [136,137] The most probable mode of MMP-2 activation inside cardiac myocytes undergoing ischemia-reperfusion injuries is via peroxynitrite Unlike the other members of the MMP family, and despite the presence of the N-terminal signal peptide, most of the MMP-26 (matrilysin-2 ⁄ endometase) produced is reported to be retained inside the cell [138,139] The conserved PRCGXPD motif in the prodomain involved in the latency of other MMPs is replaced by the unique PH81CGVPD motif in MMP26 This motif, along with other atypical structures, is assumed to facilitate autocatalytical activation of the enzyme inside the cell [140] Furthermore, it has been reported that MMP-26 has one high-affinity and one low-affinity calcium-binding site [141] Normal intracellular calcium-levels probably maintain MMP-26 in an inactive state and the active enzyme may only be seen during transient intracellular calcium influx An increased level of MMP-26 in breast cancer has been found to correlate with longer patient survival [142] This positive effect of intracellular MMP-26 is assumed to be a result of its capacity to process the estrogen receptor b [142] Storage in exocytic vesicles Polymorphonuclear leukocytes and mast cells can store MMPs, as well as other proteinases and PGs, in exocytic vesicles and release them into the extracellular environment upon activation of the cells Recent studies have shown also that endothelial cells, chondrocytes and various cancer cells can store MMPs in intracellular vesicles Endothelial cells could release MMP-2, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 very rapidly, suggesting that they originate from intracellular storage compartments The vesicle content of both pro- and active MMPs was increased by stimulation with the angiogenic factors fibroblast growth factor-2 or vascular endothelial growth factor The addition of isolated vesicles to endothelial cells increased their ability to invade and form capillary-like structures in vitro [143] Growth plate cartilage cultures have been shown to 38 produce matrix vesicles that contain both pro- and active MMP-2 and MMP-3, as well as TIMP-1 and TIMP-2 The MMP activity was strongly increased by treatment with the vitamin D metabolite 1,25(OH)2D3 Chondrocytes from growth zones produce membrane vesicles with higher MMP content than chondrocytes from resting zones, indicating that theses enzymes are involved in ECM remodeling at the hypertrophic cell zone in the growth plates of long bones [144,145] Ovarian carcinoma ascites-derived membrane vesicles have been shown to contain both pro- and active forms of MMP-2 and MMP-9, active urokinase-like plasminogen activator, MT1-MMP and urokinase-like plasminogen activator receptor Ascites from patients with late stage cancers had higher vesicle content and contained more active enzymes than ascites from patients with non-malignant lesions or early stage cancer Purified ascites vesicles were found to stimulate the invasion of cultured ovarian cancer cells through matrigel, and this invasion was markedly inhibited by the addition of either MMPI or serine proteinase inhibitors [146] Furthermore, fibrosarcoma cells are also shown to shed membrane vesicles containing both pro- and active forms of MMP-2 and MMP-9, as well as urokinase plasminogen activator [147] In oral carcinoma cells, both pro- and processed forms of MMP-9 have been found in cytoplasmic vesicular structures often co-compartmentalized with trypsin-2, an activator of proMMP-9 In addition, the same carcinoma cells expressed enterokinase, which is an activator of trypsinogen, the zymogen form of trypsin-2 This suggests the existence of an intracellular cascade where enterokinase can activate trypsin-2, which may further activate proMMP-9 The intracellularly activated MMP-9 had a slightly higher molecular weight than APMA activated MMP-9, which may represent intermediate forms that are more susceptible to full activation after secretion [148] In melanoma cells, MMP-2 and MMP-9 have been detected in a high number of small, vesicular organelles organized along the microtubular network The two enzymes were not colocalized, but were often found in close proximity to each other A high degree of overlapping distribution was seen between the MMP-2 positive vesicles, the motor protein kinesin and a-tubulin within the cells Treatment of the cells with a microtubule-interfering drug impaired the secretion of MMP-2 and MMP-9 [149] Taken together, these studies indicate that various cell types can store pro- and active MMP-2 and MMP-9, as well as their activators, intracellularly in small exocytic vesicles These vesicles may be actively propelled along FEBS Journal 278 (2011) 28–45 ª 2010 The Authors Journal compilation ª 2010 FEBS E Hadler-Olsen et al microtubules towards the plasma membrane by the motor protein kinesin Shedding of such vesicles may be a way of achieving rapid, directional proteolysis during cell migration, invasion or during 3D morphological organization in the process of angiogenesis Concluding remarks Post-translational regulation of MMP activity is complex and involves various macromolecular interactions These interactions may direct the enzymes to specific compartments in the extracellular environment, to the cell surface or to intracellular sites Furthermore, such interactions may concentrate the enzymes close to or on target substrates, and can also affect the activation of inactive proenzymes The binding of MMPs to other macromolecules may also regulate the activity of the enzymes either through stabilization or through induction of autodegradation Enzyme activity may be regulated through binding partner interactions that includes noncatalytic or exosites, and thereby inhibit or prevent the processing of a 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(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

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