Matrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003).
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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 protiens, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signalling, 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.
Collagen fibril diameter and spatial organisation are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005).
The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).
Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.
Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).
Alpha 2-macroglobulin (A2M) is a plasma glycoprotein consisting of 4 near-identical subunits (Andersen et al. 1995). A2M inhibits almost all endopeptidases regardless of their specificities (Barrett 1981). A2M binding to an endopeptidase is triggered by cleavage of a peptide bond in the 'bait region' of A2M, triggering a conformational change in A2M that in turn entraps the peptidase without blocking the active site (Barrett & Starkey 1973). This blocks enzyme activity against large protein substrates while not preventing activity on low molecular weight substrates.
Once bound, A2M-proteinase complexes are endocytosed by low density lipoprotein receptor-related protein-1 (LRP1) (Strickland et al. 1990).
Active metalloproteinases (MMPs) that can be entrapped by A2M include MMP3 (Enghild et al. 1989) MMP1 (Grinnell et al. 1998) and MMP 13 (Beekman et al. 1999).
The significance of this mechanism as a regulator of MMP activity is unclear (Baker et al. 2002, Nagase et al. 2006).
Certain normally extracellular MMPs can transiently localize at the cell periphery in association with adhesion receptors or proteoglycans. ProMMP9, MMP9, MMP2 and MMP7 (Ahmed et al. 2002, Samanna et al. 2006, Yu et al. 2002) localize at the cell membrane with the single-pass transmembrane glycoprotein CD44, known to be involved in hyaluronan-cell interactions, lymphocyte homing and cell adhesion (Toole 1990). Membrane-associated MMP7 can bring about the shedding of several membrane proteins such as epidermal growth factor (EGF), soluble Fas ligand (FasL), E-cadherin and TNF-alpha from their membrane-bound precursors, thereby promoting cancer progression (Li et al. 2006). MMP9 is able to cleave CD44, inhibiting cell migration and reducing the malignant potential of tumour cells (Chetty et al. 2012).
E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.
The elastin component of elastic fibres is degraded to soluble fragments by MMP2 (Murphy et al. 1991), MMP7 (Quantin et al. 1989, Murphy et al. 1991), MMP9 (Murphy et al. 1991, Katsuda et al. 1994) and MMP12 (macrophage elastase) (Shapiro et al. 1993, Taddese et al. 2008), and to a limited extent by MMP3 and 10 (Murphy et al. 1991). In addition, elastin is a substrate for neutrophil elastase (Reilly & Travis 1980). Eighty-nine tropoelastin cleavage sites were identified for MMP-12, whereas MMP-7 and MMP-9 were found to cleave at only 58 and 63 sites, respectively (Heinz et al. 2010).
Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Keratinocytes of the skin secrete numerous laminin isoforms, including laminin-511 and laminin-332.
Laminin-332 undergoes extensive proteolysis following secretion, which is essential for laminin-332 integration into the BM (Rousselle & Beck 2013). The 200 kDa alpha-3 subunit of laminin-332 is cleaved between the LG3-LG4 subdomains to generate a 165 kDa product. The 160 kDa gamma-2 subunit is cleaved at its N-terminus to produce a 105 kDa protein (Marinkovich et al. 1992). Tissue remodeling may lead to further proteolysis of the 105 kDa subunit within the N-terminus giving rise to a 80 kDa protein (Gianelli et al. 1997, Koshikawa et al. 2005). The resulting N-terminal fragment has EGF-like properties and may activate the EGF receptor, inducing cell migration (Schenk et al. 2003).
MMP1 can degrade fibronectin (Fukai et al. 1995), as can MMP3 (Gunja-Smith et al. 1985, Nicholson et al. 1989, Wilhelm et al. 1993, Fukai et al. 1995), MMP7 (Quantin et al. 1989, Miyazaki et al. 1990, Fukai et al. 1995, von Bredow et al. 1995), MMP10 (Nicholson et al. 1989), MMP12 (Gronski et al. 1997), MMP13 (Knauper et al. 1997), MMP14 (Shi & Sottile 2011) and 19 (Stracke et al. 2000). Cathepsin S is able to degrade fibronectin (Taleb et al. 2006). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) suggesting that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004).
Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
Aggrecan (large aggregating proteoglycan, chondroitin sulfate proteoglycan 1) is a major structural component of cartilage, particularly articular cartilage. The core protein has over 100 chains of chondroitin sulphate and keratan sulphate giving a MWt of about 250 kDa. The core protein has 2 N-terminal globular domains G1 and G2 and a C-terminal globular G3 domain. G2 and G3 are separated by a region heavily modified with negatively charged glycosaminoglycans (GAGs). The two main modifier moieties keratan sulfate (KS) and chondroitin sulfate (CS) are arranged into two CS regions and a KS-rich region. The 15-kDa interglobular linker (IGD) between the N-terminal G1 and G2 domains is particularly susceptible to proteolysis (Caterson et al. 2000). Degradation in this region is associated with the development of osteoarthritis (Troeberg & Nagase 2012). Members of the ADAM (A Disintegrin And Metalloprotease) protein family are responsible for this cleavage (East et al. 2007, Huang & Wu 2008).
Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn341~Phe342 bond (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as others towards the C-terminus. However, the the majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala373 (numbered here according to the UniProt sequence, these residues referred to as Glu373-Ala374 in most literature) in the IGD (Sandy et al. 1992). ADAMTS5 (aggrecanase-2, Abbaszade et al. 1999) and to a lesser extent ADAMTS4 (aggrecanase-1, Tortorella et al. 1999) are primarrily responsible (Gendron et al. 2007) though the preferred cleavage sites of these are in the CS-2 domain. ADAMTS1 (Kuno et al. 2000, Rodriques-Manzaneque et al. 2002), 9, (Somerville et al. 2003), 8 (Colins-Racie 2004), 16 and 18 (Zeng et al. 2006) can also degrade aggrecan in vitro.
HSPG2 protein (perlecan) consists of a core protein of molecular weight 470 kDa with three long glycosaminoglycan (GAG) chains attached, each approximately 70-100 kDa. These are usually heparan sulphate (HS), but can be chondroitin sulphate (CS). The core protein consists of five distinct structural domains. The N-terminal domain I (aa ~1-195) contains attachment sites for GAG chains. Although GAG chains are not required for correct folding and secretion of the protein, lack of GAG or decreased sulfation can decrease perlecan's ability to interact with matrix proteins. Removal of GAG chains may affect matrix organization and endothelial barrier function.
The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. For example, HS-bound FGF was released from cultured cells by treatments with MMP3, rat MMP13, and plasmin (Whitelock et al. 1996). Other MMPs reported to degrade HSPG2 include MMP14 and MMP15 (d'Ortho et al. 1997). MMP12 releases chondroitin sulphate and heparan sulphate from basement membranes (Gronski et al. 1997) and degrades the related aggrecan (Durigova et al. 2011) so may degrade perlecan. Corneal epithelium explant growth correlates with MMP2 expression, an initial degradation of the original basement membrane, and an initial upregulation followed by downregulation of MMP9. However this may not result from direct cleavage of HSPG2 by these MMPs, they may modulate some factor involved in the maturation of basement membrane (Li et al. 2006). The core protein of HSPG2 can be cleaved by cathepsin S (Liuzzo et al. 1999).
All mammals have three fibrillin genes (Davis & Summers 2012). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. Fibrillin-1 is the major structural component of microfibrils (Kielty et al. 2005). Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 was isolated from and is predominantly expressed in brain; it is not known whether it forms microfibrils (Corson et al. 2004). Fibrillin-1 and -2 are degraded by MMP2, 9, 12 and 13 (Ashworth et al. 1999, Hindson et al. 1999). Fibrillin-1 is additionally degraded by MMP3 (Ashworth et al. 1999), the membrane-associated MMP14 (Ashworth et al. 1999), neutrophil elastase (ELANE) (Kielty et al. 1994), cathepsin L2 (V) and cathepsin K (Kirschner et al. 2011).
Fibrillin-1 is the major structural component of microfibrils (Kielty et al. 2005). It can be degraded by the membrane-associated MMP14 (Ashworth et al. 1999).
Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Laminin-511 (alpha-5 beta-1gamma-1) is a major structural component of many basement membranes (BMs) including the BM that separates the epidermis from the dermis (Määttä et al. 2001). MMP14 (MT1-MMP) has been shown to cleave the alpha chain of laminin-511, promoting tumor cell migration (Bair et al. 2005). Loss of laminin-511 is a likely contributor to age-related hair loss (Pouliot et al. 2002).
MMP14 (MT1-MMP) can degrade fibronectin (Shi & Sottile 2011). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) and suggest that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004).
Transmembrane protease serine 6 (Matriptase-2, TMPRSS6) is a transmembrane serine proteinase able to hydrolyze endogenous proteins such as type I collagen, fibronectin, and fibrinogen (Velasco et al. 2002).
Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors. For example, HS-bound FGF was released from cultured cells by treatments with MMP3, rat MMP13, and plasmin (Whitelock et al. 1996). The core protein of HSPG2 can be cleaved by cathepsin S (Liuzzo et al. 1999).
E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.
HSPG2 protein (perlecan) consists of a core protein of molecular weight 470 kDa with three long glycosaminoglycan (GAG) chains attached, each approximately 70-100 kDa. The GAG chains of HSPG2 bind growth factors in the ECM, and serve as co-ligands or ligand enhancers when bound to receptors.
MMP14 and MMP15 (MT1-MMP and MT2-MMP) can degrade HSPG2 (d'Ortho et al. 1997).
DCN consists of a core protein of ?40 kDa attached to a single chondroitin or dermatan sulfate glycosaminoglycan (GAG) chain. It interacts with collagen types I, II (Vogel et al. 1984), III (Witos et al. 2011), VI (Bidanset et al. 1992) and XIV (Ehnis et al. 1997).
DCN acts as a sink for all three isoforms of TGF-Beta, binding them while already bound to collagen (Markmann et al. 2000). Degradation of DCN by matrix metalloproteinases MMP2, 3 or 7 results in the release of TGF-beta (Imai et al. 1997). In addition, DCN binds to EGFR (Iozzo et al. 1999) causing prolonged down-regulation of EGFR-mediated mobilization of intracellular calcium (Csordás et al. 2000).
E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2.
Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment termed CTF3.
Basigin (BSG, CD147, EMPRIN) is a glycoprotein expressed on the surface of most tumor cells. It stimulates stromal cells to produce elevated levels of several matrix metalloproteinases (MMP), including interstitial collagenase (MMP1). MMPs have been implicated in several aspects of tumor progression, including invasion through basement membranes and interstitial matrices, angiogenesis, and tumor cell growth. Basigin not only stimulates the production of MMP1 but also forms a complex with MMP1 at the tumor cell surface. This interaction may be important in modifying the tumor cell pericellular matrix to promote invasion.
Plasma fibronectin (FN1) is degraded by cathepsin G (CTSG) into a characteristic pattern of gelatin-binding peptides of M, = 64000, 40000, and 30000 (Vartio et al. 1981, Vartio 1982). CTSG is activated by UV exposure and can activate matrix metalloproteinases MMP1 and MMP2, but increased levels of MMP activity did not correlate with increased FN degradation in normal human fibroblasts (NHFs) following exposure to UVB (50 mJ/cm2) irradiation, while addtion of CTSG inhibitor decreased FN degradation, suggesting that CTSG is directly responsible for FN1 degradation (Son et al. 2009).
ADAM8 can cleave fibronectin in human cartilage extracts at Ala271/Val272, within a linker region between the fifth and sixth type I domains, producing ?30-kd and ?50–85-kd fragments with distinctive neoepitopes VRAA271 and 272VYQP that are associated with osteoarthritis (Zack et al. 2006, 2009).
Brevican, a member of the lectican family, is one of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM.
Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000). The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010).
Brevican, a member of the lectican family, is one of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM. Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000).
The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican (MMP-1, -2, -3, -7, -8, -10, -13 and -19) preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010).
Laminins are an important molecular component of the basement membranes (BMs) in a variety of tissue types. They have a cruciform shape, and are composed of three chains, alpha, beta and gamma., all of which have multiple subtypes. At the ultrastructural level, each laminin trimer appears as a cross-like structure with a large globular domain (LG domain) at the base of the cross. The LG domain is the C-terminal domain of the alpha subunit; it is divided into five homologous subdomains LG1-5 (Sugawara et al. 2008). Keratinocytes of the skin secrete numerous laminin isoforms, including laminin-511 and laminin-332.
Laminin-332 undergoes extensive proteolysis following secretion, which is essential for laminin-332 integration into the BM (Rousselle & Beck 2013). The 200 kDa alpha-3 subunit of laminin-332 is cleaved between the LG3-LG4 subdomains to generate a 165 kDa product. The 160 kDa gamma-2 subunit is cleaved at its N-terminus to produce a 105 kDa protein (Marinkovich et al. 1992). Tissue remodeling may lead to further proteolysis of the 105 kDa subunit within the N-terminus giving rise to a 80 kDa protein (Gianelli et al. 1997, Koshikawa et al. 2005). The resulting N-terminal fragment has EGF-like properties and may activate the EGF receptor, inducing cell migration (Schenk et al. 2003).
In much of the early literature it is not clear which subunit of the laminin trimer was cleaved, but in vitro studies have revealed specific enzymes involved in the processing of laminin-332 including MMP2, MMP14 (MT1-MMP), and the C-proteinase family of enzymes, especially bone morphogenic protein 1 (BMP1) and mammalian tolloid (mTLD), isoforms 1 and 3 respectively of UniProt P13497 BMP1 (Sugawara et al. 2008, Rousselle & Beck 2013).
The beta-3 and gamma-2 chains of laminin-322 are degraded by matrix metalloproteinase 14 (MMP14, MT1-MMP, Udayakumar et al. 2003, Koshikawa et al. 2000, 2005, Pirilä et al. 2003).
Aggrecan (large aggregating proteoglycan, chondroitin sulfate proteoglycan 1) is a major structural component of cartilage, particularly articular cartilage. The core protein has over 100 chains of chondroitin sulphate and keratan sulphate giving a MWt of about 250 kDa. The core protein has 2 N-terminal globular domains G1 and G2 and a C-terminal globular G3 domain. G2 and G3 are separated by a region heavily modified with negatively charged glycosaminoglycans (GAGs). The two main modifier moieties keratan sulfate (KS) and chondroitin sulfate (CS) are arranged into two CS regions and a KS-rich region. The 15-kDa interglobular linker (IGD) between the N-terminal G1 and G2 domains is particularly susceptible to proteolysis (Caterson et al. 2000). Degradation in this region is associated with the development of osteoarthritis (Troeberg & Nagase 2012). Members of the ADAM (A Disintegrin And Metalloprotease) protein family are believed to be largely responsible for this cleavage (East et al. 2007, Huang & Wu 2008). The majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala393 (numbering used here refers to the UniProt sequence, these residues often desgnated Glu373-Ala374 in literature) in the IGD (Sandy et al. 1992).
Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn360-Phe361 bond (numbering used here refers to the UniProt sequence, these residues often desgnated Asn341-Phe342 in literature). (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as other sites towards the C-terminus.
Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1.
Endorepellin is the 85-kDa C-terminal domain V of HSPG2 (perlecan). It consists of a series of laminin-like globular (LG) domains interconnected by short epidermal growth factor-like repeats (Hohenester & Engel 2002). Endorepellin has angiostatic activity (Mongiat et al. 2003) which is primarily localised in the LG3 domain (Bix et al. 2004).
Bone morphogenetic protein 1 (BMP1), its isoform mammalian Tolloid (mTLD), mammalian Tolloid-like-1 and -2 (TLL1, TLL2) (Gonzalez et al. 2005) and cathepsin-L1 (Cailhier et al. 2008) can liberate LG3 by cleaving endorepellin between Asn4196 and Asp4197.
E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.
OPN is a substrate for MMP3 and MMP7. Three cleavage sites were identified, Gly166-Leu167, Ala201-Tyr202 (MMP-3 only), and Asp210-Leu211. The resulting OPN fragments facilitate adhesion and migration in vitro through activation of beta1-containing integrins (Agnihotri et al. 2001). OPN has also been shown to be a substrate for liver transglutaminase and plasma transglutaminase factor IIIa, resulting in protein crosslinking (Prince et al. 1991), enhanced cell adhesion, spreading, focal contact formation and migration
E-cadherin (CDH1) localizes to the lateral membrane of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions cross-link the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.
Calpains (EC 3.4.22.17; CAPN, Clan CA, family C02) constitute a distinct group of intracellular cysteine proteases found in almost all eukaryotes and a few bacteria. Calpains can be described as cytosolic proteases exhibiting Ca2+-dependent limited proteolytic activity which function to transform or modulate their substrate proteins' structures and activities; they are therefore called modulator proteases. As calpains selectively cleave proteins in response to calcium signals, they have the potential to influence cellular functions such as signal transduction, cytoskeletal remodelling, cell motility, membrane repair, cell cycle progression, gene expression and apoptosis (Sorimachi et al. 2010). Calpain deficiencies are linked to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy and diabetes (Sorimachi et al. 2011).
The human genome has 15 genes (named using formal nomenclature as CAPN1, CAPN2, etc.) that encode a calpain-like protease domain. The two best-characterised members of the calpain family, CAPN1 and 2, are ubiquitously expressed and locate to the cytosol of the cell (Goll et al. 2003). All other calpains annotated here are assumed to be functionally similar to these two based on their structural similarites. They are heterodimers, consisting of a common small regulatory subunit (CAPNS1 or CAPNS2; ca. 30kDa) and a large, isoform-specific catalytic subunit. Three-dimensional structural analyses reveal the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to ca. four Ca2+ ions via well-conserved amino acids. So, despite the fact that they have divergent domain structures, calpains share this mechanistic functional character (Croall & Ersfeld 2007, Sorimachi et al. 2011, Ono & Sorimachi 2012).
Calpain activity is tightly regulated by the endogenous inhibitor calpastatin (CAST), which is capable of reversibly binding and inhibiting four molecules of calpain in the presence of calcium. This suggests calpains are transiently activated by high Ca2+ concentrations such as a Ca2+ influx, and then return to an inactive state ready for reactivation (Campbell & Davies 2012).
Extracellular HTRA1 (High-temperature requirement A serine peptidase 1) catalyzes the hydrolysis of a specific peptide bond in ACAN (Aggrecan) (Chamberland et al. 2009; Hu et al. 1998). The enzyme is a homotrimer (Truebestein et al. 2011). HTRA1 is thereby implicated in the degradation of extracellular matrix. Indirect studies in mouse model systems (e.g., Oka et al. 2004) that HTRA1 may modulate the activity of Tgf-beta and thereby play additional roles, not annotated here, in the turnover of extracellular matrix both normally and during inflammation.
Opticin (OPTC) is a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). OPTC has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS4 and ADAMTS5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP2 cleaves OPTC at T87/S88 and G114/L115 (Tio et al. 2014).
Opticin (OPTC) is a a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). OPTC has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP7 cleaves recombinant human OPTN at four positions, A20/S21LP (removing the signal peptide), E32/Q33, T87/S88, and G114/L115.
Opticin (OPTC) is a a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). Opticin has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP13 cleaves recombinant bovine OPTC at G104/L105 (major product), and P109/A110 (minor product) (Montfort et al. 2008).The major cleavage site corresponds to G114/L115 in human opticin.
Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is highly expressed in osteoblasts. It can form homooligomers and heterooligomers with SCUBE1, which stably associate with the peripheral cell surface. In normal lung it is mainly expressed in bronchial epithelial cells. Its expression is upregulated in some lung cancer tumors and correlates with invasive ability in a lung cancer cell line model (Wu et al. 2004, 2011). SCUBE3 knockdown is associated with lower tumor vascular permeability, inhibiting the metastatic potential of Non-small-cell lung carcinoma (Chou et al. 2013).
SCUBE3 can be cleaved by the gelatinases Matrix metalloprotease-2 (MMP2) and MMP9, releasing two major fragments. The C-terminal fragment contains a complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. The secreted SCUBE3 protein and the C-terminal CUB domain fragment can bind the Transforming growth factor beta type II receptor (TGFBR2) and activate signaling (Wu et al. 2011). SCUBE3 may act as an FGF co-receptor, augmenting FGF8 signaling (Tu et al. 2014) .
Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016).
Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is highly expressed in osteoblasts. It can form homooligomers and heterooligomers with SCUBE1, which stably associate with the peripheral cell surface (Wu et al. 2004).
Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016).
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heterotetramer,
calpain-1matrix
Ala(271)/Val(272)The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).
Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.
Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).
dimer fragment
155-700dimer fragment
155-750dimer fragment
701-882dimer fragment
732-882dimer fragment
751-882extracellular
proteinasesdegrading extracellular
proteinasespolymer, SCUBE3
polymerAnnotated Interactions
heterotetramer,
calpain-1matrix
Ala(271)/Val(272)dimer fragment
155-700dimer fragment
155-700dimer fragment
155-700dimer fragment
155-750dimer fragment
155-750dimer fragment
701-882dimer fragment
701-882dimer fragment
701-882dimer fragment
732-882dimer fragment
751-882extracellular
proteinasesdegrading extracellular
proteinasesOnce bound, A2M-proteinase complexes are endocytosed by low density lipoprotein receptor-related protein-1 (LRP1) (Strickland et al. 1990).
Active metalloproteinases (MMPs) that can be entrapped by A2M include MMP3 (Enghild et al. 1989) MMP1 (Grinnell et al. 1998) and MMP 13 (Beekman et al. 1999).
The significance of this mechanism as a regulator of MMP activity is unclear (Baker et al. 2002, Nagase et al. 2006).
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.Eighty-nine tropoelastin cleavage sites were identified for MMP-12, whereas MMP-7 and MMP-9 were found to cleave at only 58 and 63 sites, respectively (Heinz et al. 2010).
In much of the early literature it is not clear which subunit of the laminin trimer was cleaved, but in vitro studies have revealed specific enzymes involved in the processing of laminin-332 including MMP2, MMP14 (MT1-MMP), and the C-proteinase family of enzymes, especially bone morphogenic protein 1 (BMP1) and mammalian tolloid (mTLD), isoforms 1 and 3 respectively of UniProt P13497 BMP1 (Sugawara et al. 2008, Rousselle & Beck 2013). Many proteases have been demonstrated to degrade specific subunits of laminin-332. The beta-3 chain is degraded by matrix metalloproteinase 14 (MMP14, MT1-MMP, Udayakumar et al. 2003) and MMP7 (Remy et al. 2006). The alpha-3 chain is degraded by plasmin (Goldfinger et al. 1998, 1999) and BMP1 (and its isoform mTLD, Veitch et al. 2003). Laminin gamma-2 chain is degraded by MMP14 (Koshikawa et al. 2000, 2005, Pirilä et al. 2003) , MMP2 (Gianelli et al. 1997, Pirilä et al. 2003), MMP3, 12, 13 (Pirilä et al. 2003), 19 (Sadowski et al. 2005), MMP20 (Väänänen et al. 2001, Pirilä et al. 2003), BMP1 (Amano et al. 2000, Kessler et al. 2001) and mTLD (Veitch et al. 2003). Plasmin cleavage of laminin-111 yields fragments with sizes that correspond to the cleavage of the alpha and beta/gamma components (Gutiérrez-Fernández et al. 2009).
In this reaction laminin-322 is represented with all 3 component peptides cleaved.Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn341~Phe342 bond (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as others towards the C-terminus. However, the the majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala373 (numbered here according to the UniProt sequence, these residues referred to as Glu373-Ala374 in most literature) in the IGD (Sandy et al. 1992). ADAMTS5 (aggrecanase-2, Abbaszade et al. 1999) and to a lesser extent ADAMTS4 (aggrecanase-1, Tortorella et al. 1999) are primarrily responsible (Gendron et al. 2007) though the preferred cleavage sites of these are in the CS-2 domain. ADAMTS1 (Kuno et al. 2000, Rodriques-Manzaneque et al. 2002), 9, (Somerville et al. 2003), 8 (Colins-Racie 2004), 16 and 18 (Zeng et al. 2006) can also degrade aggrecan in vitro.
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment.Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2.
Caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa C-terminal fragment termed CTF3.Laminin-332 undergoes extensive proteolysis following secretion, which is essential for laminin-332 integration into the BM (Rousselle & Beck 2013). The 200 kDa alpha-3 subunit of laminin-332 is cleaved between the LG3-LG4 subdomains to generate a 165 kDa product. The 160 kDa gamma-2 subunit is cleaved at its N-terminus to produce a 105 kDa protein (Marinkovich et al. 1992). Tissue remodeling may lead to further proteolysis of the 105 kDa subunit within the N-terminus giving rise to a 80 kDa protein (Gianelli et al. 1997, Koshikawa et al. 2005). The resulting N-terminal fragment has EGF-like properties and may activate the EGF receptor, inducing cell migration (Schenk et al. 2003).
In much of the early literature it is not clear which subunit of the laminin trimer was cleaved, but in vitro studies have revealed specific enzymes involved in the processing of laminin-332 including MMP2, MMP14 (MT1-MMP), and the C-proteinase family of enzymes, especially bone morphogenic protein 1 (BMP1) and mammalian tolloid (mTLD), isoforms 1 and 3 respectively of UniProt P13497 BMP1 (Sugawara et al. 2008, Rousselle & Beck 2013).
The beta-3 and gamma-2 chains of laminin-322 are degraded by matrix metalloproteinase 14 (MMP14, MT1-MMP, Udayakumar et al. 2003, Koshikawa et al. 2000, 2005, Pirilä et al. 2003).
Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn360-Phe361 bond (numbering used here refers to the UniProt sequence, these residues often desgnated Asn341-Phe342 in literature). (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as other sites towards the C-terminus.
Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.
Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment.
The human genome has 15 genes (named using formal nomenclature as CAPN1, CAPN2, etc.) that encode a calpain-like protease domain. The two best-characterised members of the calpain family, CAPN1 and 2, are ubiquitously expressed and locate to the cytosol of the cell (Goll et al. 2003). All other calpains annotated here are assumed to be functionally similar to these two based on their structural similarites. They are heterodimers, consisting of a common small regulatory subunit (CAPNS1 or CAPNS2; ca. 30kDa) and a large, isoform-specific catalytic subunit. Three-dimensional structural analyses reveal the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to ca. four Ca2+ ions via well-conserved amino acids. So, despite the fact that they have divergent domain structures, calpains share this mechanistic functional character (Croall & Ersfeld 2007, Sorimachi et al. 2011, Ono & Sorimachi 2012).
Calpain activity is tightly regulated by the endogenous inhibitor calpastatin (CAST), which is capable of reversibly binding and inhibiting four molecules of calpain in the presence of calcium. This suggests calpains are transiently activated by high Ca2+ concentrations such as a Ca2+ influx, and then return to an inactive state ready for reactivation (Campbell & Davies 2012).
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS4 and ADAMTS5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP2 cleaves OPTC at T87/S88 and G114/L115 (Tio et al. 2014).
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP7 cleaves recombinant human OPTN at four positions, A20/S21LP (removing the signal peptide), E32/Q33, T87/S88, and G114/L115.
OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP13 cleaves recombinant bovine OPTC at G104/L105 (major product), and P109/A110 (minor product) (Montfort et al. 2008).The major cleavage site corresponds to G114/L115 in human opticin.
SCUBE3 can be cleaved by the gelatinases Matrix metalloprotease-2 (MMP2) and MMP9, releasing two major fragments. The C-terminal fragment contains a complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. The secreted SCUBE3 protein and the C-terminal CUB domain fragment can bind the Transforming growth factor beta type II receptor (TGFBR2) and activate signaling (Wu et al. 2011). SCUBE3 may act as an FGF co-receptor, augmenting FGF8 signaling (Tu et al. 2014) . Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016).
polymer, SCUBE3
polymer