The matrix metalloproteinases (MMPs), previously known as matrixins, are classically known to be involved in the turnover of extracellular matrix (ECM) components. However, recent high throughput proteomics analyses have revealed that ~80% of MMP substrates are non-ECM proteins including cytokines, growth factor binding proteins, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signaling, and that some MMPs are beneficial and may be drug anti-targets. Thus, MMPs have important roles in many processes including embryo development, morphogenesis, tissue homeostasis and remodeling. They are implicated in several diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes. Alternate splice forms are known, leading to nuclear localization of select MMPs. Most are secreted from the cell, or in the case of membrane type (MT) MMPs become plasma membrane associated, as inactive proenzymes. Their subsequent activation is a key regulatory step, with requirements specific to MMP subtype.
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Cleaving the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). This activation is inhibited by endostatin (Nyberg et al. 2003). Residue numbering here refers to the UniProt canonical sequence.
The 42 kDa intermediate form of MMP1 is fully activated by cleavage of the Gln99-Phe100 bond, producing a 41 kDa protein. MMP2 (Crabbe et al. 1994), MMP3 (Suzuki et al. 1990, Nagase et al. 1992), MMP7 (Imai et al. 1995), MMP10 (Nicholson et al. 1989) and MMP11 (Murphy et al. 1993) are able to convert the 42 kDa intermediate to fully activated 41 kDa form though they are not able to initiate activation of proMMP1 effectively (Nagase et al. 1992). MMP3 regulates MMP1 collagenase activity in human rheumatoid synovial fibroblasts (Unemori et al. 1991).
ProMMP1 has several activators including plasmin (Eeckhout & Vaes 1977, Werb et al. 1977, Santala et al. 1999), trypsin (Grant et al. 1987, Saunders et al. 2005), plasma kallikrein (Nagase et al. 1982, Saunders et al. 2005), chymase (Saarinen et al. 1994, Suzuki et al. 1995, Saunders et al. 2005), tryptase (Gruber et al. 1989, Suzuki et al. 1995, Saunders et al. 2005), neutrophil elastase, cathepsin G (Saunders et al. 2005) and trypsin-2 (Moilanen et al. 2003). Concanavalin A (ConA) was the first cellular treatment that yielded active MMPs in culture, inducing the cellular activation of MMP1 likely through MMP14 activity (Overall and Sodek 1990).Trypsin-like serine proteinases are believed to remove 34-36 residues from the N-terminus of the secreted pro-enzyme, equivalent to positions 53-55 of the UniProt cannonical sequence which includes a signal peptide. Removal of this region is sufficient to destabilize the Cys92-Zn2+ stabilizing bond (numbered according to the Uniprot canonical sequence, Cys73 when numbered from the N terminus of the secreted peptide as typically represented in the literature) and partially activate enzyme activity. This intermediate form then undergoes autocatalysis at Thr83-Leu84 producing an MMP1 with about 20% of full collagenase activity (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. When first reported, considerable debate surrounded the activation of this archetypical MMP. Divergence of opinion resulted when competing groups studied activation in vitro using chemicals (organomercurials such as aminophenylmecuricacetate), which yield a different autolytic cleavage site in the protease susceptible loop when compared with the site cut by serine proteases such as trypsin. Different specific activities result, but in general the final autolytic cleavage site for all MMPs is the homologous Phe or Tyr at position 100 or 101. When the active enzyme commences here, full activity is realised due to the salt bridge forming between the N-terminal primary amine of the conserved Phe or Tyr with an Asp on helix C that in turn salt bridges to the active site Glu. Termini either side of this position do not result in full activity.
MMP14 (MT1-MMP) binds tissue inhibitor of metalloproteinases 2 (TIMP2) and has been isolated as a complex from the plasma membrane of HT-1080 cells (Strongin et al. 1995). This complex in turn binds proMMP2 via an interaction of the C-termini of proMMP2 and TIMP2 (Itoh et al. 1998, Butler et al. 1998). Formation of this ternary complex is critical for the subsequent activation of proMMP2.
proMMP3 is activated in a similar manner to pro MMP1 but by a large number of proteinases, including bacterial thermolysin, all cleaving within the region residues 51-56 (Woessner & Nagase 2000). This initiates autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence.
proMMP8 is activated by tissue kallikrein, leukocyte elastase, trypsin and cathepsin G (Capodici et al. 1989, Knauper et al. 1990) probably at the predicted bait region, residues 30-36.
MMP1 (Sang et al. 1995), MMP2 (Fridman et al. 1995), MMP3 (Goldberg et al. 1992, Ogata et al. 1992, Okada et al. 1992), MMP7 (Imai et al. 1995, Sang et al. 1995), MMP10 (Nakamura et al. 1998) and MMP13 (Knauper et al. 1997) activate MMP9 by a stepwise mechanism but the second cleavage is apparently not an autocatalytic event as is the case for MMP1 (Okada et al. 1992). The first site is the Glu59-Met60 bond, generating an inactive 85-86 kDa intermediate (O'Connell et al. 1994), followed by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82 kDa form of MMP9 (Okada et al. 1992, Fridman et al. 1995).
ProMMP9 binds Tissue Inhibitor of Metalloproteinases 1 (TIMP1) (Wilheim et al. 1989). By homology with the binding of TIMP2 to the MMP2 hemopexin domain, TIMP1 is thought to binds via its C domain to the MMP9 hemopexin domain. This is a two-way potential regulatory mechanism as the interaction does not prevent the free N-terminal inhibitory domain of TIMP1 from inhibiting other MMPs (Murthpy et al. 1991) while it may prevent the activation of proMMP9.
proMMP10 is similar in sequence to proMMP3 with just one residue difference in the bait region. The activation mechanism is believed to be similar, namely cleavage in the N-terminal bait region, followed by autocatalytic cleavage at His81-Phe82 (Woessner & Nagasse 2000). proMMP10 is activated by plasmin, trypsin and chymotrypsin.
The membrane-type MMPs (MT-MMPs) MMP14 (MT1-MMP) (Pei et al. 1996, Sato et al. 1996) and MMP16 (MT3-MMP) (Kang et al. 2002) are processed to an active form by furin (Yana & Weiss 2000) and PACE4 (Bassi et al. 2005) within the golgi before secretion. The other MT-MMPs MMP15 (MT2-MMP), MMP17 (MT4-MMP) (Itoh et al. 1999), MMP24 (MT5-MMP) and MMP25 (MT6-MMP) (Starr et al. 2012) are believed to undergo similar processing before membrane association.
Following initiating proteolytic cleavage by serine proteases the Cys92-Zn2+ bond is destabilized allowing autocleavage at Thr83-Leu84, generating a 42 kDa active form of MMP1 with about 20% of the activity of the 41 kDa form (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100.
proMMP13 can be activated by plasmin and trypsin initially cleaving at Lys57-Glu58 followed by autoproteolysis at Glu103-Tyr104 (Knauper et al. 1996a).
The MMP14:TIMP2 complex can efficiently bind proMMP2. Physiological concentrations of TIMP2 enhance proMMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that while MMP14:TIMP2 complexes bind proMMP2, local free MMP14 cleaves the TIMP-bound proMMP2 in the prodomain, leading to autoactivation between Asn109 Tyr110. In vivo the majority of MMP14 (MT1-MMP) is bound to TIMP2 and therefore functions as a receptor for proMMP2 (Nishida et al. 2008). Binding of TIMP-2 to proMMP2 occurs via interaction of the TIMP2 C domain (McQuibban et al. 2000) and the MMP2 hemopexin domain between hemopexin blades III and IV (Overall et al. 1999) in an interaction that is highly dependant upon the nature of the C-tail of the TIMP (Kai et al. 2002). TIMP-4 also binds the proMMP2 hemopexin domain (Bigg et al. 1997) to prevent activation by MMP14 (Bigg et al. 2001). An alternative cell surface localization mechanism exists that inhibits MMP2 activation: Cell surface Beta1 integrin binds native type I collagen, which in turn is bound by the fibronectin type II modules of MMP2 to prevent activation by MMP14 (Steffensen et al. 1998).
MMP2 can be activated by MMP1 (Crabbe et al. 1994a, Sang et al. 1996) and MMP7 (Crabbe et al. 1994b, Sang et al. 1996). MMP1 initially cleaves either Pro33-Ile34 or Asn66-Leu67. This is followed by autolytic cleavage at Asn109-Tyr110 (Crabbe et al. 1994a, Okada et al. 1990, Sang et al. 1996). MMP1 and MMP7 are not efficient activators of MMP2; significant physiological activation of proMMP2 is performed by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997, Morrison et al. 2001) and MMP16 (Takino et al. 1995). Residue numbering here refers to the UniProt canonical sequence.
MMP2 is activated by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997) and MMP16 (Takino et al. 1995). MMP14 (MT1-MMP) initially cleaves the Asn66-Leu67 bond of MMP2, followed by autocleavage of the Asn109-Tyr110 bond (Strongin et al. 1993, Atkinson et al. 1995). Residue numbering here refers to the UniProt canonical sequence.
MMP2 processing by MMP14 or MMP16 is very inefficient unless the MT-MMP has pre-bound TIMP2, which in turn binds MMP2. Physiological concentrations of TIMP2 enhance MMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that MT-MMP:TIMP2 complexes bind MMP2, but local free MT-MMP subsequently cleaves the TIMP-bound proMMP2. In vivo the majority of MMP14 is bound to TIMP2 and functions as a receptor for proMMP2 (Nishida et al. 2008). In contrast, activation of proMMP2 by MMP15 occurs in a TIMP independent manner, with TIMP2 inhibiting activation at all concentrations (Morrison et al. 2001).
Native type I collagen binds to the hemopexin C domain of MMP14, and following clustering of the enzyme together enhances proMMP2 activation (Tam et al. 2002). However, proMMP2 also binds the cell via cell surface Beta1 integrin, which binds native type I collagen which in turn is bound by the fibronectin type II modules of MMP2, preventing activation by MMP14 (Steffensen et al. 1998). ConA is the only known stimulator of cells to induce proMMP2 activation by MMP14 (Overall & Sodek 1990).
Cleavage of the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). Residue numbering here refers to the UniProt canonical sequence.
The intermediate form of MMP9 is activated by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82-kDa MMP-9 species (Ogata et al. 1992, Fridman et al. 1995).
proMMP7 (proMatrilysin-1) activation by trypsin occurs via an intermediate cleaved at Lys50-Asn51 which undergoes autocatalysis (Crabbe et al. 1992). Leukocyte elastase and plasmin partially activate MMP7 by an uncharacterized mechanism. Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009).
proMMP9 can be activated by trypsin and chymotrypsin (Sopata & Dancewicz 1974), tissue kallikrein (Tschesche et al. 1989, Desrivieres et al. 1993), cathepsin G (Murphy et al. 1980), and trypsin-2 (Sorsa et al. 1997). This appears to be a one-step activation; the single peptide bond cleaved by trypsin-2 in proMMP-9 is Arg106-Phe107. Modes of activation by other proteases are unclear. Activation is inhibited by endostatin (Nyberg et al. 2003).
After the initial cleavage of the N-terminus, MMP3 undergoes autocatalysis and cleavage of the His99-Phe100 bond (Nagase et al. 1990, 1991). Residue numbering given here is based on the UniProt canonical sequence.
Following initial activation autoproteolysis occurs at Glu103-Tyr104 (Knauper et al. 1996a,1996b). This is inhibited by endostatin (Nyberg et al. 2003).
Once cleaved at Lys50-Asn51 MMP7 undergoes autocatalysis (Crabbe et al. 1992). Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009).
The process that targets activated MT-MMPs to the plasma membrane is unclear but presumed to involve standard golgi transport mechanisms. The cytoplasmic domain of MT1-MMP is critical for the localization to discrete regions of the cell surface (Urena et al. 1999) and involved in internalization which has a regulatory role. The cytoplasmic domain mediates interactions with specific cell-surface proteins such as C1Q binding protein which may serve to direct the MMP from the golgi to the cell surface (Rozanov et al. 2002).
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MMP2 processing by MMP14 or MMP16 is very inefficient unless the MT-MMP has pre-bound TIMP2, which in turn binds MMP2. Physiological concentrations of TIMP2 enhance MMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that MT-MMP:TIMP2 complexes bind MMP2, but local free MT-MMP subsequently cleaves the TIMP-bound proMMP2. In vivo the majority of MMP14 is bound to TIMP2 and functions as a receptor for proMMP2 (Nishida et al. 2008). In contrast, activation of proMMP2 by MMP15 occurs in a TIMP independent manner, with TIMP2 inhibiting activation at all concentrations (Morrison et al. 2001). Native type I collagen binds to the hemopexin C domain of MMP14, and following clustering of the enzyme together enhances proMMP2 activation (Tam et al. 2002). However, proMMP2 also binds the cell via cell surface Beta1 integrin, which binds native type I collagen which in turn is bound by the fibronectin type II modules of MMP2, preventing activation by MMP14 (Steffensen et al. 1998). ConA is the only known stimulator of cells to induce proMMP2 activation by MMP14 (Overall & Sodek 1990).