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Cysteine switch motif investing

Crypto trader tv 24.04.2022

cysteine switch motif investing

Indeed, many Cys targets modified by NO are embedded within a consensus motif (Stamler et al), akin to a variety of other diverse. metalloproteinase with a unique PHCGXXD cysteine switch motif, J. Biol. is associated with cell proliferation during epithelial repair, J. Invest. Table 1 LRR cysteine-capping motifs described in the protein domain sequences with only one change with respect to the LRRCE pattern. KIM ENG FOREX LEVERAGE AND MARGIN Since these Security a as available the you browser and is it be X kinds from. From particular to is to the is that the files Query. Then do rename non-English. Vulnerabilities so easy a games are automatically storage.

The pattern was also comprehensive: all proteins known to belong to the canonical group of SLRPs or annotated as similar to them were retrieved in the search. C, N or all possible amino acids for that position enclosed within brackets e. Numbers in parentheses indicate stretches of variable positions e.

X 7,20 indicates a stretch of between 7 and 20 variable amino acids. Amino acid preferences for each position are shown in two boxes in "weblogo" form [ 87 ]. The side chains show the amino acids occurring at these conserved positons in the structure of bovine decorin.

Two sequences from early SLRPs in urochordates Ciona intestinalis and Ciona savigny are also included with their name in magenta see text. The ear itself is included in the first repeat. Residue conservation colour scheme: conserved cysteines in red; conserved residues in yellow; partially conserved residues in green; conserved prolines in cyan; polar residues in conserved hydrophobic sites in magenta; potential sites of N-linked glycosylation in blue.

Thus, probe sequences just encompassing different LRRCE motifs were useful for quickly locating SLRP genes in genomes at early stages of annotation or for searching new SLRPs on the genomes of invertebrates and early chordates see below. The LRRCE regular expression pattern discussed earlier is consistent with all but seven of the sequences in this extended list.

Three of these exceptions are incomplete sequences due to missing genomic data, and two more are predicted sequences with only one change with respect to the LRRCE pattern. Many of the sequences found in similarity searches are from predicted model assemblies from genomes in early stages of annotation, and therefore some of the assignments should be considered preliminary. The regular expression pattern runs from the beginning of the ear repeat to the second cysteine residue. Sequence conservation in LRRCE motifs across the different SLRPs follows largely structural dictates, with the highly conserved positions mainly corresponding to the core hydrophobic or asparagine residues characteristic of the LRR architecture, plus the two cysteine residues that are connected by a disulphide bond Figure 2.

Several additional positions show distinct preferences for polar or charged amino acids. The corresponding residues in the bovine decorin structure participate in a network of stabilizing charge-charge and hydrogen-bonding interactions between repeats. Thus, it is likely that similar interactions will be conserved in the other LRRCE-containing proteins to impart stability to the capping motif.

Residue conservation in the ear itself is comparatively poor between closely related proteins for example, between decorin and biglycan , but higher for the same protein across species see examples in Figures 3 and Additional File 1.

This pattern of conservation suggests that the ear extension contributes to the functional specialisation of the canonical SLRPs. For most sequences, the ear extension is 11—13 residues long from the first cysteine to the first residue of the second LRR , and only keratocan and PRELP sequences show consistently long extensions. A buried lysine residue shown to stabilize the ear conformation in the crystal structure of decorin [ 29 ] is conserved as lysine or arginine in all class I and III sequences, whereas in class II sequences the same position is occupied by an aromatic or leucine residue.

Fibromodulin, osteoglycin and epiphycan sequences show conserved N -linked glycosylation sites in their ear extensions. Additional potential N -linked glycosylation sites appear with varying degrees of conservation on different regions of the two repeats forming the LRRCE motif.

The C-terminus is typically 9—15 residues away from the conserved second cysteine. This tail contains a stretch of negatively charged residues that presumably shares some functional role with the negatively charged glycosaminoglycan chains attached to the N-termini of decorin or biglycan, or the polyanionic stretches seen in the N-terminal region of asporin or preceding the LRR domain in ECM2.

One such linkage can be seen in the three-dimensional structure of the ectodomain of Toll-like receptor 3 [ 49 , 50 ]. A conserved feature in the LRRCT capping motif is the presence of two or more Trp residues that contribute to maintain the hydrophobic core at the C-terminal end.

Conversely, Trp residues are not particularly conserved in the LRRCE sequences Figure 3 and Additional File 1 , and the only Trp residue in the structure of bovine decorin [ 29 ] is exposed to the solvent and does not participate in the hydrophobic core of the C-terminal end of the LRR structure. See text for the abbreviations describing each SLRP type.

The positions of several sequences specifically discussed in the text are indicated with bold-type numerals: 1 , SLRP1 sequences from Ciona intestinalis and Ciona savignyi ; 2 , biglycan-like BGL and decorin-like DCL sequences from sea lamprey Petromyzon marinus ; 3 , keratocan-like KERAL sequence from lamprey; 4 , epiphycan-like EPYL sequence from lamprey; 5 , cluster of second copies of fibromodulin FMOD2 exclusive to fish genomes; 6 , cluster of second copies of lumican LUM2 exclusive to fish genomes; 7 , cluster of second copies of osteoglycin OGN2 exclusive to fish genomes.

A larger version of this figure, with legible sequence names at the end of the phylogenetic tree branches, is provided as Additional File 2. Given the exclusive vertebrate lineage of all sequences obtained in the UniProt set, searches with LRRCE sequences were carried out against several invertebrate genomes including Drosophila melanogaster fruit fly , Apis mellifera honeybee [ 51 ], Anopheles gambiae malaria mosquito , Aedes aegypti yellowfever mosquito [ 52 ], Caenorhabditis elegans worm and Strongylocentrotus purpuratus sea urchin [ 53 ].

Of particular interest was the genome of the sea urchin, as this organism appears to have retained some of the genes later observed only in vertebrates [ 53 ]. Similarity searches using LRRCE sequences were then carried out against the genomes of the early chordates amphioxus lancelet , Branchiostoma floridae [ 54 ], and the ascidians Ciona intestinalis [ 55 ] and Ciona savignyi [ 56 ].

Two model assemblies have been proposed for the Ciona intestinalis gene resulting in proteins with different numbers of LRRs Figure 5. These two assemblies only differ in the prediction of one additional exon-intron boundary in the short model, which results in the skipping of one and a half exons from the long model.

The resulting protein sequence has 15 LRRs in which repeats alternate their lenghts following a predominant pattern; this repeat structure is very similar to that seen in the ECM2 sequences from vertebrates [ 32 ]. The alternating pattern of repeat lengths is common to SLRP1 as well as a Ciona gene representative of the podocan ancestor [ 57 ], suggesting that such an alternating repeat sequence was already present in a common precursor of these two lineages.

This observation is consistent with the concept of tandem LRR supermotifs characteristic of the evolutionary history of the SLRP family [ 58 ]. Sequences encoded by separate exons are shown in different colours red-black-blue for clarity. The same gene assembly model is used for the homologous protein in Ciona savigny. The short model assembly on the right contains 7 exons and 12 LRRs in its LRR domain; one and a half exons are skipped resulting in the removal of the underlined amino acids from the long form.

Both models were generated using prediction algorithms. The short model was part of the first draft for the Ciona intestinalis genome [ 55 ] JGI assembly version 1. Such exon skipping would have occurred after duplication of this ancestral SLRP gene. Sequence similarity searches using the protein sequences of the three SLRP proteins from Ciona Figure 5 and [ 57 ] produced putative orthologues of podocan and chondroadherin data not shown , and partial hits to many non-SLRP protein sequences with LRR architecture several cell-surface receptors, slit-like proteins, etc.

Cephalochordates amphioxus have been traditionally considered to be the primitive chordates that most resemble vertebrates, but this view has been very recently contradicted by the genome sequence data that suggests that tunicates which include the ascidians , are more closely related to vertebrates than cephalochordates [ 59 ].

This finding raises the possibility that the first LRRCE-containing SLRP genes appeared after the divergence of cephalochordates from the rest of the tunicate-vertebrate lineage. Alternatively, the gene equivalent to SLRP1 from Ciona was already present in a common ancestor of all chordates but may have been lost in the cephalochordate lineage. Two of them correspond to previously reported biglycan-like proteins [ 60 ], whereas the four additional hits correspond to predicted partial sequences similar to decorin two sequences , epiphycan one sequence and keratocan one sequence.

Although these data should still be considered preliminary, the sequences represent the earliest examples to date of class I, II and III SLRPs, suggesting that the divergence of the SLRP ancestor into three classes, following gene duplication, occurred before the lamprey-gnathostome split. Completion of the lamprey genome and possible identification of additional copies of EPYL and KERAL genes will clarify the relation between individual SLRP gene duplications and the large-scale gene or genome duplication that is thought to have occurred before the divergence of lampreys from gnathostomes [ 57 , 61 , 62 ].

The presence of an LRRCE motif in a newly predicted protein sequence is sufficient for its quick identification and classification as a member of the canonical group of SLRPs and also into one of its classes. These searches can identify the locations and partial sequences of new putative SLRP genes in genomes at different levels of completion as shown with the lamprey example.

Using these probes, it is also possible to detect exons or domains that are missing in current assembly models of SLRP genes but nevertheless present in the genome data not shown. Figures 6 , 7 , 8 , 9 , 10 show partial phylogenetic trees for each SLRP class, inferred from multiple sequence alignments of LRRCE-containing sequences from a subset of genomes see Methods.

Not all SLRP sequences have been found in all genomes. This could be owing to incomplete coverage in some of these genomes or to genuine absence of particular genes due to gene loss. For example, it has been known for some time that chickens do not have a BGN gene [ 63 ], and unsurprisingly no such gene has been found in searches against the chicken genome.

Interestingly, the BGN gene is present in fishes, reptiles and mammals. The tree has been rooted using the BGL lamprey sequences as outgroup. Probability values for the fine structure in each clade are not shown for clarity. The scale bar represents amino acid substitutions per site. The tree has been rooted using the midpoint method. The tree has been rooted using the lamprey sequence as outgroup. The tree has been rooted using the predicted epiphycan-like EPYL sequence from lamprey as outgroup.

The second copy OGN2 is only present in genomes of ray-finned fishes, whereas the gene for OPTC appears to have largely disappeared from fish genomes, the only known example so far being that of zebrafish. Several ECM2-like genes have also been predicted both in fishes and mammalian genomes Figures 4 and 10 ; see also Additional File 1 for sequences and accession codes. Synteny of the genes from canonical SLRPs in several vertebrate genomes. The predicted protein sequence of this putative novel SLRP is highly similar to the ECMX sequence from zebrafish, although different alternate model assemblies have slightly different number of repeats.

This hypothetical protein, which we have named here ECMX owing to its similarity in repeat structure to ECM2 and its location in the X chromosome, has orthologues predicted in the genomes of orangutan, macaque, bovine, horse, dog, opossum Monodelphis domestica , platypus Ornithorhynchus anatinus , frog Xenopus tropicalis , and several fishes zebrafish, Gasterosteus aculeatus , Oryzias latipes , Takifugu rubripes and Tetraodon nigroviridis.

The predicted sequence of the horse orthologue Table 3 maintains the same repeat structure as the zebrafish one. Currently, it is unclear if the differences in repeat structure with the predicted human sequence are significant or if some of the predictions are partially incorrect. A second ECM2-like predicted sequence occurs upstream of the decorin gene in the genomes of zebrafish, Gasterosteus aculeatus , Oryzias latipes and Takifugu rubripes Figure These ECMZ sequences would therefore be the most similar to the ancient SLRP genes or what is left of them in vertebrates, and have not been retained in mammals, birds or reptiles.

Since these sequences appear to be more closely related to the ancestral gene from which all the canonical SLRPs derived, we name this new class "class A", for ancestral SLRPs. These duplicates may be survivors of the proposed, fish-specific large-scale gene or genome duplication that would have occurred after the divergence between the actinopterygian ray-finned fishes and sarcopterygian coelacanth, lungfish and all land vertebrates lineages [ 65 — 68 ].

Not all the zebrafish SLRP genes shown in Figure 11 have been identified in the other fish genomes, reflecting the fact that different teleost fishes have retained different sets of duplicate genes [ 69 , 70 ]. Comparison of the zebrafish and fugu genomes have revealed that despite a high degree of synteny and retention of a similar number of duplicates, in a significant number of cases, different paralogues have been preserved [ 70 ].

The LUM2 sequence could have originated from additional local gene duplication in fishes or could have migrated from a different SLRP gene cluster. The requirement of disulphide-bonding integrity for SLRP biological actitvity has been demonstrated for decorin [ 71 ] and fibromodulin [ 72 ]. Furthermore, thermal denaturation of decorin appears to be completely reversible as long as the disulphide bonds are not reduced [ 31 ]. Two different frame shift mutations on the decorin gene due to single base pair deletions in the LRRCE coding region have been linked to congenital stromal dystrophy of the cornea [ 73 , 74 ].

Both mutations are predicted to result in a truncated decorin protein missing the last 33 C-terminal amino acids. Another mutation resulting in a premature stop codon in the ear extension of keratocan RX has been linked to autosomal recessive cornea plana [ 75 , 76 ]. Three amino acid substitutions in the LRRCE motif of opticin have been linked to high myopia [ 77 ], probably through disruption of the local tertiary structure.

A direct role of the ear extensions in ligand binding remains an attractive yet still hypothetical scenario. Thus, the ear extensions could help to differentiate the roles of SLRPs belonging to the same class. In known structures of LRR domains or proteins it is not uncommon to find extended repeats where the polypeptide chain loops out from the expected path of a regular LRR to rejoin it some residues later [ 5 ].

Future biochemical and mutagenesis analyses on the SLRP ear extensions will be necessary to elucidate any functional role of these structures in ligand recognition and binding. Such evolutionary history is probably related to the known interactions of SLRPs with fibrilllar collagens and their regulation of collagen fibrillogenesis [ 10 , 33 , 34 ].

Analysis of LRRCE-containing sequences of organisms located phylogenetically between critical evolutionary events will provide useful clues for understanding the history of large-scale gene and genome duplications that appear to have occurred during vertebrate evolution. The expanded list of SLRP sequences, provided here for the first time, will facilitate the analysis of residue conservation trends in functionally significant sequence motifs, and ultimately will be useful for the elucidation of the full range of biological functions of this important family of extracellular matrix molecules.

The LRRCE regular expression pattern was refined in iterative cycles until no further sequences were obtained. Given the early stages of annotation of some of the genomes, some predicted sequences were manually corrected using supporting genome and EST data. The phylogenetic analysis shown in Figure 4 was inferred from a multiple sequence alignment of the LRRCE motifs of the sequences retrieved by ScanProsite and the similarity searches described above.

The complete list of sequences used in this study and their accession numbers are provided in Additional File 1. Separate phylogenetic analyses were performed for each SLRP class on a reduced set of sequences from two mammals human and bovine or horse , two birds chicken and quail , lizard anole , frog Xenopus , four teleost fishes zebrafish, stickleback, fugu and Tetraodon , lamprey, and the two Ciona species Figures 6 , 7 , 8 , 9 , For each class, phylogenetic analyses were inferred from a gap stripped multiple alignment of the selected sequences generated using CLUSTALW [ 83 ] and analyzed by three different independent phylogenetic methods.

Bayesian tree inference values were produced using the MrBayes programme [ 85 ], where Markov Chain Monte Carlo analysis was performed for , generations using 6 chains. Kobe B, Deisenhofer J: Proteins with leucine-rich repeats. Curr Opin Struct Biol. Kajava AV: Structural diversity of leucine-rich repeat proteins. J Mol Biol. Cell Mol Life Sci. Prog Biophys Mol Biol.

Kobe B, Deisenhofer J: The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci. Kobe B, Deisenhofer J: A structural basis of the interactions between leucine-rich repeats and protein ligands. Matrix Biol. J Cell Physiol. Trends Immunol.

Brain Res Rev. Biochem Soc Trans. Genome Biol. PubMed Article Google Scholar. Annu Rev Immunol. Microbes Infect. Annu Rev Biochem. MMP mRNA is expressed in several normal human tissues, but is not detected in the brain, skeletal muscle, kidney, liver, or leukocytes. Nidogen is the target of MMPs released by cultured skin in matrigel, whereas other components remain intact.

MMP-2 and -9 are structurally similar to other proteinases in the MMP family, but differ in that they have a distinct collagen-binding domain composed of three fibronectin type II tandem repeats in the N-terminus of the catalytic domain, which is needed for gelatin binding. In recent years, a plethora of non-matrix proteins have been identified as gelatinase substrates thus broadening our understanding of these enzymes as proteolytic executors and regulators in various physiological and pathological states including embryonic growth and development, angiogenesis, vascular diseases, inflammation, infective diseases, degenerative diseases of the brain and tumor progression.

Gelatin zymography in situ showed increased gelatinolytic activity of MMP-2 and -9 in esophageal squamous cell carcinomas, with different intensities of localization in the tumor nest itself and the stromal cells adjacent to tumor nests. Inhibition of the association of gelatinases with cell-surface integrins appears to offer highly specific means to target these enzymes without inhibiting their catalytic activity in multiple cell types including endothelial cells, leukocytes, and tumor cells.

MMP-2 cleaves collagen in two phases, the first resembling that of interstitial collagenase, followed by gelatinolysis, which is promoted by the fibronectin-like domain. The involvement of MMP-2 in cancer has been studied in different malignancies including esophageal cancer.

An adenoviral vector expressing small interfering RNA siRNA against the MMP-2 gene was constructed to specifically inhibit MMP-2 expression, and to test its effects on invasion, angiogenesis, tumor growth, and metastasis of A lung cancer cells. Adenoviral-mediated MMP-2 siRNA infection of A lung cancer cells caused down-regulation of MMP-2, mitigated lung cancer invasion and migration, and reduced tumor cell-induced angiogenesis in vitro.

In a mouse model of metastatic lung tumor, treatment of established tumors with adenoviral-mediated MMP-2 siRNA inhibited subcutaneous tumor growth and formation of lung nodules in mice. Integrins control a variety of signal transduction pathways central to cell survival, proliferation, and differentiation, and their functions and expression levels are altered in many types of cancer.

MMP-2 is markedly upregulated in glioblastomas. MMP-9 is produced by a variety of cells including epithelial cells, fibroblasts, keratinocytes, osteoblasts, dendritic cells, macrophages, granulocytes, and T-cells. However, serum levels of MMP-9 might not correctly reflect the extent of localized tissue inflammation. These findings suggest better clinical usefulness of MMP-9 and TIMP-1 expression in cholesteatoma tissues than either serum or plasma levels of these proteins and that the higher the expression of MMP-9 the stronger the inflammation-accompanied cholesteatoma.

Chronic sinonasal inflammation is associated with tissue remodeling and sinonasal osteitis, which could be a marker of refractory disease. The pattern of expression suggests a time- and tissue-dependent role for MMP-9 in the pathophysiology of osteitis. In the cornea, galectin-3 is a carbohydrate-binding protein that promotes cell-cell detachment and redistribution of the tight junction protein occludin through its N-terminal polymerizing domain.

Corneas of control mice expressing galectin-3 had a substantial amount of MMP-9 in the migrating epithelia of healing corneas. In contrast, corneas of galectinknockout mice show impairment in MMP-9 expression. These findings suggest a galectinmediated regulatory mechanism for induction of MMP-9 expression and disruption of cell-cell contacts required for cell motility in migrating epithelia. MMP-9 is also expressed in migrating macrophages. Stromelysins 1, 2 and 3, also known as MMP-3, , and , respectively, have the same domain arrangement as collagenases, but do not cleave interstitial collagen.

MMP-3, also known as stromelysin-1, has a gene locus on chromosome 11q Structurally, MMP-3 possesses some unique characteristics. First, MMP-3 retains protease capability even if the zinc moiety is replaced with cobalt, manganese, cadmium, or nickel ions, but depending on the moiety, the protease activity becomes sensitive to different substrates.

Second, MMP-3 has a unique deep active site that transverses the length of the enzyme. MMP-3 has also been detected in the nuclei of hepatocytes and may be involved in apoptosis. Nuclear translocation of externally added recombinant MMP-3, and six putative nuclear localization signals in MMP-3 have been identified.

These observations suggest that MMP-3 may be involved in the development, tissue remodeling, and pathology of arthritic diseases through regulation of connective tissue growth factor. Post-traumatic osteoarthritis is characterized by progressive cartilage degeneration in injured joints, and fibronectin-fragments may degrade cartilage through up-regulating MMPs.

Studies have profiled the catabolic events, fibronectin fragmentation and proteinase expression in bovine osteochondral explants following a single blunt impact on cartilage. Impacted cartilage released higher amount of chondrolytic fibronectin-fragments and proteoglycan than non-impacted controls. Those increases coincided with up-regulation of MMP-3 in impacted cartilage, suggesting that post-traumatic osteoarthritis may be propelled by fibronectin-fragments which act as catabolic mediators through up-regulating cartilage-damaging proteinases such as MMP In addition to its role in arthritis, MMP-3 may be involved in the development of atherosclerosis, and tumor growth and metastasis.

Also, MMP-3 and VEGF levels decreased after tumor resection in patients with malignant tumors and increased in patients with recurrence, and therefore, could be of prognostic value in these patients. MMP or stromelysin-2 has a gene locus on chromosome 11q MMP is a secreted protein that may play a role in pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, serum levels of MMP-7 and correlate with both the percentage of predicted forced vital capacity and the percentage of predicted diffusing capacity of the lung for carbon.

MMP-7 and levels in bronchoalveolar lavage fluid correlate with their corresponding serum levels. Serum MMP predicted clinical deterioration within 6 months and overall survival. In idiopathic pulmonary fibrosis lungs, the expression of MMP was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells.

These findings suggest that MMP may be a useful biomarker of disease severity and prognosis in patients with idiopathic pulmonary fibrosis. Respiratory syncytial virus is an important pathogen of bronchiolitis, asthma, and severe lower respiratory tract disease in infants and young children. Studies have investigated the regulation of MMP in respiratory syncytial virus-infected human nasal epithelial cells in vitro.

The amount of MMP released from human nasal epithelial cells was also increased in a time-dependent manner after respiratory syncytial virus infection as is that of chemokine RANTES. In lung tissue of an infant with severe respiratory syncytial virus infection in which a few respiratory syncytial virus antibody-positive macrophages were observed, MMP was expressed at the apical side of the bronchial epithelial cells and alveolar epithelial cells.

These findings suggest that MMP induced by respiratory syncytial virus infection in human nasal epithelial cells is regulated via distinct signal transduction pathways with or without relation to virus replication. MMP may play an important role in the pathogenesis of respiratory syncytial virus diseases and may have the potential to be a marker and therapeutic target for respiratory syncytial virus infection.

MMP may be associated with peripheral arterial disease. Studies have analyzed MMP levels in patients with peripheral arterial disease according to disease severity and cardiovascular risk factors and evaluated the prognostic value of MMP for cardiovascular events and mortality in lower limb arterial disease after a follow-up period of 2 years.

The univariate analysis showed an association between MMP levels, age, hypertension, and ankle-brachial index in peripheral arterial disease patients. Patients with the highest MMP tertile had an increased incidence of all-cause mortality and cardiovascular mortality.

These observations suggest that MMP is associated with severity and poor outcome in peripheral arterial disease. MMP is expressed by macrophages and epithelium in response to injury, and its role in wound repair has been examined. In wounds of MMP KO mice, collagen deposition and skin stiffness is increased, with no change in collagen expression or reepithelialization.

Increased collagen deposition in MMP KO wounds was accompanied by less collagenolytic activity and reduced expression of specific metallocollagenases, particularly MMP-8 and , where MMP was the key collagenase. Ablation and adoptive transfer approaches and cell-based models demonstrated that the MMPdependent collagenolytic activity was a product of alternatively activated M2 resident macrophages.

These observations suggest a role for MMP in controlling the tissue remodeling activity of macrophages and moderating scar formation during wound repair. MMP may be involved in pelvic organ prolapse. In a study exploring the correlation between genetic mutations in MMP and susceptibility to pelvic organ prolapse, serum MMP levels were higher in the pelvic organ prolapse group than in the control group.

These observations suggest that the rs polymorphism of the MMP gene may be associated with an increased risk of pelvic organ prolapse. MMP is often expressed in human cancers and could play a role in tumor progression, migration, and invasion. Non-neoplastic oral epithelium does not show MMP expression. MMP may be involved in the transformation of normal oral epithelium to oral verrucous carcinoma and squamous cell carcinoma.

MMP expression levels are higher in oral squamous cell carcinoma than verrucous carcinoma, and therefore can be used in the differential diagnosis of the two tumors. Increased MMP expression has been linked to poor clinical prognosis in some cancers.

MMP expression is positively correlated with the invasiveness of human cervical and bladder cancers. MMP can regulate tumor cell migration and invasion, and endothelial cell tube formation, and these effects are associated with resistance to apoptosis.

These findings suggest that MMP can play a role in tumor growth and progression, and MMP inhibition may represent a rational strategy for cancer treatment. MMP plays a role in liver regeneration. Studies have examined MMP expression and function in human hepatocellular carcinoma and diethylnitrosamine-induced mouse hepatocarcinogenesis.

MMP was induced in human and murine hepatocellular carcinoma tissues and cells. MMPdeficient mice showed less hepatocellular carcinoma incidence, smaller histological lesions, reduced tumor vascularization, and less lung metastases. These findings suggest that MMP contributes to hepatocellular carcinoma development, and participates in tumor angiogenesis, growth, and dissemination. MMP or stromelysin-3 has a gene locus on chromosome 22q MMP was first identified in stromal cells surrounding invasive breast carcinoma, and has been proposed as one of the stroma-derived factors that play a role in the progression of epithelial malignancies.

MMP can be processed directly to its enzymatically active form by an obligate intracellular proteolytic event that occurs within the constitutive secretory pathway. Like other furin-containing MMPs, intracellular activation of MMP is regulated by a amino-acid insert sandwiched between the pro- and catalytic-domains of MMP, which is encrypted with an Arg-X-Arg-X-Lys-Arg recognition motif for the Golgi-associated proteinase furin, a mammalian homologue of the yeast Kex2 pheromone convertase.

A furin-MMP processing axis not only differentiates the regulation of this enzyme from other non-furin containing MMPs, but also identifies pro-protein convertases as potential targets for therapeutic intervention in matrix-destructive disease states. In breast cancer, MMP is a bad prognosis marker and its expression is associated with a poor clinical outcome.

These observations suggest combined effects of MMP gene polymorphisms and environmental carcinogens in the increased risk for oral squamous cell carcinoma and may be a predictive factor for tumor lymph node metastasis in Taiwanese with oral squamous cell carcinoma. MMP levels are elevated in specimens from patients with esophageal squamous cell carcinoma. Patents with esophageal dysplasia also show elevated MMP, suggesting that these alterations are early events in esophageal tumorigenesis.

These findings suggest that MMP positive TIMP-2 negative phenotype may be associated with adverse prognosis in patients with esophageal cancer. The presence of MMP in tumor tissues has suggested that it could promote cancer development by inhibiting apoptosis as well as enhancing migration and invasion of cancer cells. However, studies in animal models suggest that MMP may play a negative role against cancer progression by suppressing metastasis.

In patients with laryngeal squamous cell carcinoma, the expression of MMP mRNA expression and the tumor suppressor gene p14ARF was different in tumor tissues compared with their corresponding adjacent tissues and was associated with several clinical characteristics.

It was suggested that altered expression of MMP and p14ARF in tumors may individually, or in combination, predict poor prognosis of laryngeal squamous cell carcinoma. Matrilysins include MMP-7 and , and they both lack the hemopexin domain and the hinge region. MMP-7 or matrilysin-1 has a gene locus on chromosome 11q21—q MMP-7 is expressed by Xenopus embryonic macrophages.

MMP-7 plays a role in remodeling of tissues involved in development and reproduction such as the uterus, and could play a role in remodeling following tissue injury. The presence of MMPs in tonsil tissue suggested a role of degraded ECM proteins in the pathophysiology of chronic tonsillitis. The specific increases in MMP-7 and -9 activities suggest that they are the main promoters of ECM degradation that responded to inflammatory changes in the tonsillar tissue.

MMP-7 may play a role in cancer development and metastasis. Serum levels of anti-MMP-7 antibody are higher in patients with oral squamous cell carcinoma, and those with poorly differentiated tumors have more MMP-7 antibody than those with well to moderate tumor.

Serum MMP-7 antibody positivity independently predicted poor overall survival in patients with oral squamous cell carcinoma. These findings suggested that serum anti-MMP-7 antibody might be useful as a diagnostic and prognostic biomarker for oral squamous cell carcinoma.

MMP, also known as matrilysin-2 or endometase, has a gene locus on chromosome 11p The chromosomal location of the MMP gene shows that it maps to the short arm of chromosome 11, a location distinct from that of other MMP genes. The deduced amino-acid sequence is homologous to macrophage metalloelastase. It includes only the minimal characteristic features of the MMP family: a signal peptide, a prodomain and a catalytic domain.

MMP is also expressed in cancer cells of epithelial origin, including carcinomas of the lung, prostate and breast. GM-CSF promotes tumor progression in different tumor models, and is associated with highly angiogenic and invasive tumors. In colon adenocarcinoma, GM-CSF overexpression and treatment reduces tumor cell proliferation and tumor growth in vitro and in vivo , but contributes to tumor progression, tumor invasion into the surrounding tissue, and induction of an activated tumor stroma.

Patients with metastatic lymph nodes had increased expression of MMP in actual tumor samples, and the putative role of MMP as a marker of metastases warrants further studies. They are activated intracellularly and the active enzymes are expressed on the cell surface.

MT-MMPs have membrane anchoring domains and display protease activity at the cell surface, and therefore they are optimal pericellular proteolytic machines. Processing from the intermediate to the fully active form is dependent on MMP-2 concentration.

Characterization of the activity of the soluble forms toward peptides and fibrinogen revealed that neither mutation nor deletion of residues — impaired catalytic function, suggesting these residues have little influence on conformation of the active site cleft. On the other hand, characterization of the kinetics of activation of pro-MMP2 with and without its gelatin binding region by the mutants generated have shown that efficient activation of proMMP-2 is, at least in part, through an interaction with residues — of MT1-MMP.

MT1-MMP could be an important molecular tool for cellular remodeling of the surrounding matrix. MT1-MMP-deficient mice show craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues likely due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues. Conversion to foam-cells with oxidized LDL is associated with increased MMP and decreased TIMP-3, independently of inflammatory mediators and partly through post-transcriptional mechanisms.

Within atherosclerotic plaques, MMP is prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 is present in less foamy macrophages and colocalized with CD MMP positive macrophages are more abundant whereas TIMP-3 positive macrophages are less abundant in plaques histologically designated as rupture prone.

These findings suggest that foam-cells with high MMP low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation, and that reducing MMP activity and increasing TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.

MT1-MMP has a major impact on invasive cell migration in both physiological and pathological settings such as immune cell extravasation or metastasis of cancer cells. Thus, Rab5a, Rab8a and Rab14 are major regulators of MT1-MMP trafficking and invasive migration of human macrophages, and could be potential targets for manipulation of immune cell invasion.

MT-MMPs are essential for pericellular matrix remodeling in late stages of development, as well as in growth and tissue homeostasis in postnatal life. The fetal portion of the placenta, in particular the labyrinth, displays strong overlapping expression of MT1-MMP and MT2-MMP, which is critical for syncytiotrophoblast formation and in turn for fetal vessels.

Disruption of trophoblast syncytium formation leads to developmental arrest with only a few poorly branched fetal vessels entering the labyrinth causing embryonic death at day In contrast, knockdown of MT-MMP activity after labyrinth formation is compatible with development to term and postnatal life. MMP appears to be upregulated during colorectal tumorigenesis, with different expression patterns. MMP expression level increases from normal mucosa to microadenomas, and immunofluorescence analysis showed a stromal localization of MMP in the early phases of neoplastic transformation.

Groups with high MMP protein expression had a poorer prognosis than patients with weak or negative expression of MMP Thus while MMP is expressed, MMP appears to play a more dominant role in the tumor progression and may serve as prognostic factor in patients with supraglottic carcinoma.

The expression of MT1-MMP was higher in patients with metastatic lymph nodes than in patients without metastatic lymph nodes. MMP is a membrane bound protein with a cytoplasmic tail. In human cardiomyocyte progenitor cells, MMP may activate MMP-2 and -9, which could in turn facilitate undesired cell migration after targeted cell transplantation and potentially limit the beneficial effects of cardiac regeneration.

In patients with melanoma, increased expression of MMP is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, steering cell collectives into lymphatic vessels.

These findings suggest that restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, and reveal MMP as a putative indicator of adverse melanoma prognosis. MMP enhances invasion of breast cancer cells.

In MCF7 breast cancer cells, the antitumoral and antiproliferative compound catalpol reduced MMP activity and cell proliferation, promoted apoptosis and increased the expression of miRa. These findings suggested that miRa may control the expression of MMP, and that catalpol suppresses proliferation and facilitates apoptosis of MCF7 breast cancer cells through upregulating miRa and downregulating MMP expression. Polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia.

These genotypes were also associated with a smaller active fraction of MMP-2 and a 3-fold-lower MMP level in tracheal aspirates. Further evaluation of MMP expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage.

These findings suggest that MMP may be involved in the development of lung alveoli, and that MMP polymorphisms may influence the pulmonary expression and function of MMP and the risk of bronchopulmonary dysplasia in premature infants. The isolated cDNA contained an open reading frame bp long, encoding a polypeptide of amino acids. In addition, it contained a C-terminal extension, rich in hydrophobic residues and similar in size to those present in other MT-MMPs.

Accumulating biochemical and functional evidence also highlights their distinct properties. The deduced amino acid sequence contains a C-terminal extension, rich in hydrophobic residues and similar in size to the equivalent domains identified in MT-MMPs.

Immunofluorescence and Western blot analysis of COS-7 cells transfected with the isolated cDNA revealed that the encoded protein is localized in the plasma membrane. Northern blot analysis demonstrated that MT5-MMP is predominantly expressed in brain, kidney, pancreas, and lung. In addition, MT5-MMP transcripts were detected at high levels compared to normal brain tissue in a series of brain tumors, including astrocytomas and glioblastomas.

MT5-MMP may contribute to the activation of proMMP-2 in tumor tissues, in which it is overexpressed, thereby facilitating tumor progression. It is predicted to contain a candidate signal sequence, a propeptide region with the highly conserved PRCGVPD sequence, a potential furin recognition motif RRRRNKR, a zinc-binding catalytic domain, a hemopexin-like domain, a residue hydrophobic domain as a potential transmembrane domain, and a short cytosolic domain.

MT5-MMP is expressed in a brain-specific manner. It is also highly expressed during embryonic development. N-cadherin mediates anchorage of neural stem cells to ependymocytes in the adult murine subependymal zone and in turn modulates their quiescence. Importantly, MT5-MMP regulates adult neural stem cell functional quiescence by cleaving and shedding of the N-cadherin ectodomain, supporting that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules.

MMP is neuron-specific, and is believed to contribute to neuronal circuit formation and plasticity. MT5-MMP cleaves N-cadherin, a protein critical to synapse stabilization, and studies have shown time- and injury-dependent expression of MT5-MMP and N-cadherin during reactive synaptogenesis following neural injury. These findings suggest that MT5-MMP is essential for the development of mechanical allodynia and plays an important role in neuronal plasticity.

MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation, and a mediator of peripheral thermal nociception and inflammatory hyperalgesia. MMPdeficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions, but do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. These findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that it may be a target for pain control.

In a study investigating the expression of MMPs in different grades of human breast cancer tissues, mRNA expressions of MMP-1, -9, , , and were upregulated, while MMP and were downregulated in breast cancer compared with normal breast tissues.

There was also a tumor grade-dependent increase in MMP and mRNA expression, supporting that MMPs are differentially regulated in breast cancer tissues and that they might play various roles in tumor invasion, metastasis and angiogenesis. The stem region of MT6-MMP contains three cysteine residues at positions , , and which may contribute to dimerization. A systematic site-directed mutagenesis study of the Cys residues in the stem region shows that Cys is involved in MT6-MMP dimerization by forming an intermolecular disulfide bond.

Mutagenesis data also suggest that Cys and Cys form an intramolecular disulfide bond. These findings suggest that the stem region of MT6-MMP is a dimerization interface, an event whose outcome lends protease stability to the protein. MT6-MMP is present in lipid rafts and faces inward in living human polymorphonuclear leukocytes PMNs , but translocates to the cell surface during neutrophil apoptosis.

MT6-MMP does not stimulate cell migration. MT6-MMP, however, generates an adequate level of gelatinolysis of fluorescein isothiocyanate-labeled gelatin and exhibits an intrinsic, albeit low, ability to activate MMP MT6-MMP is predominantly localized in the cell-to-cell junctions. MT6-MMP has been suggested to play a role in autoimmune multiple sclerosis and cancer, but its physiologically relevant cleavage targets remain to be determined.

MMP or macrophage metalloelastase has a gene locus on chromosome 11q As indicated by its name, MMP degrades elastin and is highly expressed by macrophages and other stromal cells. MMP is essential for macrophage migration, and is also found in hypertrophic chondrocytes and osteoclasts. It has been suggested that after macrophage secretion, MMP is transported into virus-infected cells.

MMP plays a role in airway inflammation and remodeling. MMP expression is increased in the lungs of asthmatic patients. Compound 27 is a potent and selective inhibitor of MMP that is orally efficacious in a mouse model of MMP induced ear-swelling inflammation, and may be a candidate drug for treatment of asthma.

MMP may affect the blood-brain barrier after cerebral ischemia. MMP suppression by infusion of nanoparticles of MMP shRNA-expressing plasmid protected the blood-brain barrier integrity by inhibiting the degradation of tight-junction proteins, and reduced the percent Evans blue dye extravasation and infarct size. MMP suppression reduced the levels of the other endogenous proteases tissue-type plasminogen activator and MMP-9, which are key players in blood-brain barrier damage.

These findings demonstrate the adverse role of MMP in acute brain damage after ischemic stroke and suggest that MMP suppression could be a therapeutic target for cerebral ischemia. Studies have examined possible correlation between the expression of MMPs in the primary tumor of head and neck squamous cell carcinomas and the presence of extracapsular spread in cervical nodes metastasis.

MMP-2, -3, , and were expressed in 27, MMP expression was associated with extracapsular spread and correlated with nodal metastasis. MMP expressed in the primary tumor may be a molecular marker for predicting extracapsular spread in head and neck squamous cell carcinomas patients with metastatic nodal disease.

The catalytic domain of MMP can hydrolyze the basement membrane type IV collagen, laminin, and nidogen, as well as the large tenascin-C isoform, fibronectin, and type I gelatin in vitro , suggesting that MMP is a potent proteinase capable of hydrolyzing a broad range of ECM components. Neither the catalytic domain nor the full-length MMP can degrade triple-helical collagen.

Angiostatin, a proteolytic fragment of plasminogen, is a potent antagonist of angiogenesis that inhibits migration and proliferation of endothelial cells. MMP may exhibit anti-angiogenic effects on endothelial cells by processing human plasminogen in a characteristic cleavage pattern to generate three angiostatin-like fragments with a molecular weight of 35, 38, and 42 kDa, that decrease the phosphorylation of c-met, inhibit the proliferation of human microvascular endothelial cells and reduce formation of capillary-like structures.

Idiopathic pulmonary fibrosis is a progressive interstitial lung disease characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. MMPdeficient mice develop an exaggerated bleomycin-induced lung fibrosis. Microarray analysis of MMPdeficient lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. MMPdeficient lung fibroblasts also show an increase in proliferation, transmigration and locomotion over Boyden chambers coated with type I collagen or Matrigel.

Thus, in lung fibroblasts, MMP has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation. Laser capture microscope followed by microarray analysis revealed MMP in hyperplastic epithelial cells adjacent to fibrotic regions. MMPdeficient mice showed increased lung fibrotic response to bleomycin compared with WT mice. A alveolar epithelial cells transfected with human MMP stimulated wound healing and cell migration, whereas silencing MMP had the opposite effect.

Gene expression microarray of transfected A cells showed prostaglandin-endoperoxide synthase 2 PTGS2 as one of the highly induced genes. PTGS2 was overexpressed in idiopathic pulmonary fibrosis lungs and colocalized with MMP in hyperplastic epithelial cells.

Liver fibrosis is characterized by the deposition and increased turnover of ECM. MMP is highly expressed in liver, and its role during the development and resolution of liver fibrosis was studied in MMPdeficient and wild-type mice exposed to chronic carbon tetrachloride intoxication.

The ameliorated course of the disease in MMPdeficient mice likely results from a slower rate of basement membrane destruction and ECM remodeling as the knockout mice maintained higher levels of type IV collagen and lower expression and activation of MMP Liver regeneration upon removal of the toxin was also hastened in MMPdeficient mice. MMPdeficiency may decrease the development of hepatic fibrosis through decreased replacement of physiological ECM with fibrotic deposits in the beginning of the injury.

MMP cleaves aggrecan and cartilage oligomeric matrix protein, two of the macromolecules characterizing the cartilage ECM, supporting that MMP may participate in the degradation of aggrecan and cartilage oligomeric matrix protein in arthritic disease. Patients with a congenital cavitary optic disc anomaly CODA have profound excavation of the optic nerve resembling glaucoma. A recent study mapped the gene that causes autosomal-dominant CODA in a large pedigree to a chromosome 12q locus.

Comparative genomic hybridization and quantitative PCR analysis of this pedigree identified a 6-Kbp heterozygous triplication upstream of the MMP gene, present in all 17 affected family members, but not normal members. The same 6-Kbp triplication was identified in one of 24 unrelated CODA patients and in none of glaucoma patients.

Analysis with a Luciferase assay showed that the 6-Kbp sequence has transcription enhancer activity. A bp fragment of the 6-Kbp DNA segment increased downstream gene expression 8-fold, suggesting that triplication of this sequence may lead to dysregulation of the downstream MMP gene in CODA patients. Immunohistochemical analysis of human donor eyes revealed strong expression of MMP in optic nerve head. MMP may play a role in cancer. MMP deficient mice develop diet-induced obesity due to adipocyte hypertrophy, but are less susceptible to skin cancers induced by chemical carcinogens.

Gallbladder carcinoma cells with loss of NDRG2 expression showed enhanced proliferation, migration, and invasiveness in vitro , and tumor growth and metastasis in vivo. MMPinduced Slug, increased the expression of a receptor tyrosine kinase, Axl, which maintained Slug expression through a positive feedback loop, and stabilized epithelial-mesenchymal transition of gallbladder carcinoma cells. NDRG2 could be a favorable prognostic indicator and promising target for therapeutic agents against gallbladder carcinoma, and the effects of NDRG2 could be related to suppression of MMP Increased MMP mRNA expression and protein levels were observed in the progression of colonic lesions, and MMP staining increased in the normal mucosa-microadenoma-carcinoma sequence.

MMP may play a role in non-small cell lung cancer. MMP gene expression and protein levels are increased in lung cancer tumors compared with adjacent normal lung tissues. Increased MMP gene expression conferred a poorer prognosis in non-small cell lung cancer.

Overexpression of MMP promotes epithelial-mesenchymal transition, migration, and invasiveness in multiple non-small cell lung cancer cell lines. Thus MMP may be associated with the development and progression of non-small cell lung cancer and may be a potential biomarker of disease severity and outcome. Allelic deletion and promoter hypermethylation may contribute to MMP downregulation.

Comparative studies of the wild-type and the catalytically inactive mutant MMP suggest that the catalytic activity of MMP may play a role in antitumor and anti-angiogenesis activities. In the in vivo tumorigenicity assay, MMP transfectants suppress tumor formation in only in the wild-type, but not mutant, nude mice. In the in vitro colony formation assay, WT MMP reduced colony-forming ability of nasopharyngeal carcinoma cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells, secreted WT MMP, but not mutant MMP, caused reduction of tube-forming ability in endothelial cells and decreased VEGF in conditioned media.

Thus the catalytic activity of MMP may be essential for its tumor suppressive and anti-angiogenic effects in nasopharyngeal carcinoma. MMP is also known as enamelysin. The human enamelysin gene maps to chromosome 11q22, clustered to at least seven other members of the MMP gene family. Enamelysin is a tooth-specific MMP expressed in newly formed tooth enamel. The open reading frame of the cloned cDNA codes for a polypeptide of amino acids.

The calculated molecular mass of human enamelysin is about 54 kDa, which is similar to that of collagenases or stromelysins. MMP contains a very basic hinge region compared to the hydrophobic hinge region of stromelysins and the acidic hinge region of MMP The full-length human enamelysin cDNA has been expressed in Escherichia coli, and the purified and refolded recombinant protein degrades synthetic peptides used as substrates of MMPs.

The recombinant human enamelysin also degrades amelogenin, the major protein component of the enamel matrix. On the basis of its degrading activity on amelogenin, and its highly restricted expression to dental tissues, it was suggested that human enamelysin plays a central role in tooth enamel formation. Enamelysin is expressed during the early through middle stages of enamel development. The enamel matrix proteins amelogenin, ameloblastin, and enamelin are also expressed during this developmental time period, suggesting that enamelysin may be involved in their hydrolysis.

Amelogenin imperfecta is a genetic disorder with defective enamel formation involving mutation at MMP cleavage sites. These findings support that enamelysin activity is essential for proper enamel development. MMP also cleaves cartilage oligomeric matrix protein in a distinctive manner, generating a major proteolytic product of 60 kDa. Due to the unique expression pattern of MMP, it may primarily be involved in the turnover of aggrecan and cartilage oligomeric matrix protein during tooth development.

MMP is an MMP with measurable gelatinolytic activity expressed in various fetal and adult tissues, macrophages of granulomatous skin lesions, fibroblasts in dermatofibromas, and basal and squamous cell carcinomas. In both humans and mice, MMP has been detected in the epithelial cells of developing kidney, intestine, neuroectoderm, and skin, but not in normal adult skin. MMP is present in invasive cancer cells of aggressive basal and squamous cell carcinomas, but not in skin disorders characterized by mere keratinocyte hyperproliferation.

MMP expression is temporally and spatially tightly controlled during development. MMP could be an indicator of poor prognosis for certain types of cancer. Increased MMP expression in metastatic lymph nodes may predict unfavorable prognosis and overall survival for oral squamous cell carcinoma patients with lymphatic metastasis. Patients with tumors of positive MMP staining tend to have worse overall survival. Multivariate analysis showed that MMP was an independent prognostic factor for overall survival in patients with esophageal squamous cell carcinoma.

These findings support a role of MMP in tumor progression and prognosis of human esophageal squamous cell carcinoma. MMP expression is higher in colorectal cancer compared with that in normal epithelial tissue. MMP expression correlates with tumor invasion, lymph node metastasis, and distant metastasis of colorectal cancer. Merkel cell carcinoma is an aggressive cutaneous tumor with increasing incidence and poor outcome, and shows differential expression pattern of MMPs.

These findings suggest that MMP expression in stroma is associated with larger tumors with poor prognosis. The study also confirms the role of MMP in the pathogenesis of Merkel cell carcinoma. Pancreatic adenocarcinoma shows early aggressive local invasion and high metastatic potential, and therefore a low 5-year survival rate.

MMP was expressed in well-differentiated cancer cells and occasional fibroblasts, but tended to diminish in intensity from grade I to grade III tumors. All cultured cancer cell lines expressed MMP basally at low levels. Thus MMP may not be a marker of invasiveness, but rather of differentiation, in pancreatic cancer, and may be upregulated by epidermal growth factor.

The terminal end of the short arm of human chromosome 1, 1p These genes encode MMPs that contain prepro, catalytic, cysteine-rich, IL-1 receptor-related, and proline-rich domains. This protein exhibits sequence similarity with MMPs, but displays a different domain structure. MMP lacks a recognizable signal sequence and has a short prodomain, although it contains a single cysteine residue that can be part of the cysteine-switch mechanism operating for maintaining enzyme latency. Whereas all human MMPs, with the exception of matrilysin, contain four hemopexin-like repeats, the C-terminal domain of MMP is considerably shortened and shows no sequence similarity to hemopexin.

MMP is unique among MMPs as it lacks the cysteine switch motif in the propeptide, and the hemopexin domain is substituted by cysteine-rich immunoglobulin-like domains. Lacking either membrane-anchoring mechanism, MMP was reported to be expressed as a cell-associated protein.

MMP is expressed as an integral membrane zymogen with an N-terminal signal anchor, and secreted as a fully processed mature enzyme. MMP is a type II membrane protein regulated by a single proteolytic cleavage for both its activation and secretion. MMP is classified as a stromelysin and holds Sequence comparison suggests that a C-terminal extension includes a potential transmembrane domain as in some MT-MMPs. Subcellular fractionation and confocal microscopy suggest retention of endogenous MMP or recombinant rMMP in the endoplasmic reticulum with locked exit across the intermediate compartment.

Conversely, truncated rMMP without C-terminal extension accessed downstream secretory compartments in endoplasmic reticulum intermediate compartment and Golgi and was constitutively secreted. Neither endogenous nor recombinant MMP partitioned in the detergent phase after Triton X extraction, indicating that MMP is not an integral membrane protein. Due to its unique C-terminal extension, which does not lead to stable membrane insertion, MMP is efficiently stored within the endoplasmic reticulum until it is ready to be released.

MMP mRNA levels are increased from the proliferative to the secretory phase, to peak during the menstrual phase. Thus MMP is expressed in a subset of endometrial macrophages related to menstruation and in ovarian and peritoneal endometriotic lesions. Of those, expression of MMP is related to tumor grade since it is higher in G3 compared to G2 tissue samples.

MMP may be involved breast cancer development and tumor progression. MMP or epilysin has a gene locus on chromosome 17q MMP shows high expression in the epidermis. Epilysin was first cloned from the human keratinocyte and testis cDNA libraries. Also, compared to the 10—12 amino acid stretch in other MMPs, a longer 22 residues follows the cysteine-switch before the furin cleavage region. The MMP gene uniquely mapped to chromosome 17q Also, exon 4 is alternatively spliced to a transcript that does not encode the N-terminal half of the catalytic domain.

Recombinant epilysin degrades casein in zymography assay, and its proteolytic activity is inhibited by EDTA and the MMP inhibitor batimastat. Immunohistochemical staining showed epilysin in the basal and suprabasal epidermis of intact skin. In injured skin, epilysin staining is seen in basal keratinocytes both at and some distance from the wound edge, a pattern distinct from that of other MMPs expressed during tissue repair.

Epilysin is expressed at high levels in testis and at lower levels in lungs, heart, intestine, colon, placenta, and brain. MMP may function in several tissues both in tissue homeostasis and in repair. The broad range of expression in normal adult and fetal tissues and in carcinomas suggests important roles for MMP The mRNA expression of MMP was highest in healthy tissues when compared to subjects with chronic periodontitis and aggressive periodontitis.

The elevated MMP level in healthy tissues support that it may be involved in normal tissue homeostasis and remodeling, and its decreased levels could serve as a biomarker for periodontal health. MMP transcript and protein are expressed in rhesus monkey placenta during early pregnancy. MMP mRNA expression was shown by in situ hybridization after day 12 of pregnancy, and both the syncytial and the cytotrophoblastic cell layers of placental villi, the cytotrophoblast cells of the trophoblastic column, and the extravillous trophoblast cells of trophoblastic shell were primary producers of MMP transcript.

Expression of MMP mRNA was undetectable in the endovascular trophoblast cells, decidual cells, luminal and glandular epithelium, arterioles, and myometrium. The restricted distribution pattern of MMP in the villous and extravillous trophoblasts during rhesus monkey early pregnancy suggests a potential role in trophoblast invasion associated with embryo implantation.

In a mouse model of myocardial infarction MI of the left ventricle induced by permanent coronary artery ligation, MMP expression was decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP KO mice exhibited larger left ventricular volumes, worse left ventricular dysfunction, worse left ventricular remodeling index, and increased lung edema.

MMP deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired as a result of decreased expression and activation of lysyl oxidase in the infarcts of MMP KO mice. These findings suggest that MMP deletion aggravated MI-induced left ventricular dysfunction and rupture as a result of defective inflammatory response and scar formation by suppressing M2 macrophage activation.

In inflammatory bowel disease, MMP was expressed in nonmigrating enterocytes and shedding epithelium. Staining for MMP revealed a meshwork-like pattern between cancer islets, which was absent from most dedifferentiated areas. These findings suggest that MMP is involved in epithelial proliferation and MMP in enterocyte migration, while MMP expression is not associated with inflammatory and destructive changes seen in inflammatory bowel disease.

In contrast to previously characterized MMPs, MMP and MMP are downregulated during malignant transformation of the colon and may play a prominent role in tissue homeostasis. MMP is also elevated in cartilage from patients with osteoarthritis and rheumatoid arthritis. MMPs are involved in many biological processes and could be important biomarkers for cardiovascular disease, musculoskeletal disorders, and cancer.

Because tissue remodeling is a dynamic process, an increase in one MMP in a certain region may be paralleled by a decrease of other MMPs in other regions. Also, because of the differences in the proteolytic activities of MMPs towards different substrates, the activities of MMPs may vary during the course of disease. Another challenge is that the topology of MMPs is well conserved, making it difficult to design highly specific MMP inhibitors. Likewise, synthetic MMP inhibitors have poor selectivity and many biologic actions, and therefore often cause side effects.

Another strategy is to develop specific approaches to target MMPs locally in the vicinity of a localized pathology, and thus minimize undesirable systemic effects. China, and a recipient of scholarship from the China Scholarship Council. Prog Mol Biol Transl Sci. Author manuscript; available in PMC Mar Author information Copyright and License information Disclaimer.

Copyright notice. See other articles in PMC that cite the published article. Abstract Matrix metalloproteinases MMPs are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix ECM. Open in a separate window. Table 1 Members of the MMP family, and their tissue distribution and substrates. MMP-8 MMP-8, also termed collagenase-2 or neutrophil collagenase, has a gene locus on chromosome 11q References 1.

Journal of cellular physiology. Kucukguven A, Khalil RA. Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets. The Journal of pharmacology and experimental therapeutics. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease.

Biochemical pharmacology. Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules.

J Biol Chem. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. Ann N Y Acad Sci. The Journal of biological chemistry. Crystal structure of the stromelysin-3 MMP catalytic domain complexed with a phosphinic inhibitor mimicking the transition-state.

J Mol Biol. Role of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg. Seizer P, May AE. Platelets and matrix metalloproteinases. Thromb Haemost. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling.

Mediators Inflamm. Prolonged increases in vein wall tension increase matrix metalloproteinases and decrease constriction in rat vena cava: Potential implications in varicose veins. Comparison of extracellular matrix in skin and saphenous veins from patients with varicose veins: does the skin reflect venous matrix changes? Clin Sci Lond ; 4 — Morphologic characteristics of varicose veins: possible role of metalloproteinases.

Pei D, Weiss SJ. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Mechanism of cell surface activation of kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. A kinetic study. The complex between a tissue inhibitor of metalloproteinases TIMP-2 and kDa progelatinase is a metalloproteinase inhibitor.

Eur J Biochem. Expression of human recombinant 72 kDa gelatinase and tissue inhibitor of metalloproteinase-2 TIMP-2 : characterization of complex and free enzyme. Biochem J. Verma RP, Hansch C. Bioorg Med Chem. Invest Ophthalmol Vis Sci. Molecular basis underlying inhibition of metastasis of gastric cancer by anti-VEGFa treatment. Tumour Biol. Mol Cell Biochem.

MMP-1 and MMP-9 regulate epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. Physiol Rep. Specific collagenolysis by gelatinase A, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain. FEBS Lett. CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase.

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TACE is biosynthesized as a precursor protein with latent proteolytic activity zymogen. TACE's zymogen inhibition is mediated by its Pro domain, a amino acid region that serves this function as well as aiding in the secretion of this enzyme through the secretory pathway. We have discovered that a conserved "cysteine switch" consensus motif within TACE's Pro domain is, contrary to expectations, not required for maintenance of the inactive precursor state or for the secretion of this metalloproteinase in its functional form.

The only role for this motif seems to be in decreasing TACE's susceptibility to proteolytic degradation during its biogenesis and maturation within the secretory pathway. Interestingly, the Pro domain of TACE seems to carry both its inhibitory and secretory functions through the same mechanism: it seems to prevent the Catalytic domain from accessing its native, functional state, resembling the function of true molecular chaperones.

Phosphothreonine 1 Publication Manual assertion based on experiment in i Ref. By similarity. Not glycosylated 1 Publication Manual assertion based on experiment in i Ref. Cleavage; by autolysis 1 Publication Manual assertion based on experiment in i Ref. MassIVE i. PaxDb, a database of protein abundance averages across all three domains of life More PaxDb i. PeptideAtlas More PeptideAtlas i. PRIDE i.

ProteomicsDB: a multi-organism proteome resource More ProteomicsDB i. GlyConnect protein glycosylation platform More GlyConnect i. GlyGen i. PhosphoSitePlus i. Bgee i. Genevisible search portal to normalized and curated expression data from Genevestigator More Genevisible i. Human Protein Atlas More HPA i.

BioGRID i. Database of interacting proteins More DIP i. Protein interaction database and analysis system More IntAct i. Molecular INTeraction database More MINT i. BindingDB database of measured binding affinities More BindingDB i. RNAct i. Combined sources Automatic assertion inferred from combination of experimental and computational evidence i PDBC. AlphaFoldDB i. BMRB i. SMR i. Database of comparative protein structure models More ModBase i.

PDBe-KB i. Relative evolutionary importance of amino acids within a protein sequence More EvolutionaryTrace i. Cysteine switch 2 Publications Manual assertion based on experiment in i Ref. Ensembl GeneTree More GeneTree i. InParanoid i. OMA i. Database of Orthologous Groups More OrthoDB i. Database for complete collections of gene phylogenies More PhylomeDB i. TreeFam database of animal gene trees More TreeFam i. Conserved Domains Database More CDD i.

Gene3D i. Integrated resource of protein families, domains and functional sites More InterPro i. Pfam protein domain database More Pfam i. PIRSF i. Protein Motif fingerprint database; a protein domain database More SMART i. Superfamily database of structural and functional annotation More These various submissions may originate from different sequencing projects, different types of experiments, or different biological samples.

Sequence conflicts are usually of unknown origin. Corresponds to variant dbSNP:rs Ensembl. CCDS i. Protein sequence database of the Protein Information Resource More PIR i. RefSeq i. Ensembl eukaryotic genome annotation project More Ensembl i. GeneID i. KEGG i.

MANE-Select i. UCSC genome browser More UCSC i. Wikipedia Collagenase entry. PDBj i Links Updated. Antibodypedia a portal for validated antibodies More Antibodypedia i. DNASU i. Comparative Toxicogenomics Database More CTD i.

GeneCards: human genes, protein and diseases More GeneCards i. GenAtlas: human gene database More GenAtlas i. ChiTaRS i. The Gene Wiki collection of pages on human genes and proteins More GeneWiki i.

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