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43-464: Matrix metalloproteinases ( MMPs ), also known as matrix metallopeptidases or matrixins , are metalloproteinases that are calcium -dependent zinc -containing endopeptidases ; other family members are adamalysins , serralysins , and astacins . The MMPs belong to a larger family of proteases known as the metzincin superfamily . Collectively, these enzymes are capable of degrading all kinds of extracellular matrix proteins, but also can process

86-449: A divalent cation , usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are histidine, glutamate, aspartate or lysine and at least one other residue is required for catalysis, which may play an electrophilic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of

129-433: A broad-spectrum MMP inhibitor, and cipemastat (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials . The failure of Marimastat was partially responsible for the folding of British Biotech , which developed it. The failure of these drugs has been due largely to toxicity (in particular, musculo-skeletal toxicity in the case of broad spectrum inhibitors) and failure to show expected results (in

172-476: A family of four protease inhibitors : TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Synthetic inhibitors generally contain a chelating group that binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates , carboxylates , thiols , and phosphinyls . Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation of

215-464: A key process involved in cancer metastasis. MMP degradation of the ECM affects cellular behavior through changes in integrin -cell binding, by releasing growth factors harbored by the ECM, by generating ECM degradation products, and by revealing cryptic binding sites in ECM molecules. For instance, MMP-2 degradation of collagen type I can reveal a previously inaccessible cryptic binding site that binds with

258-978: A number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors , the release of apoptotic ligands (such as the FAS ligand ), and chemokine / cytokine inactivation. MMPs are also thought to play a major role in cell behaviors such as cell proliferation , migration ( adhesion /dispersion), differentiation , angiogenesis , apoptosis , and host defense . They were first described in vertebrates in 1962, including humans, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors , their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence . MMPs were described initially by Jerome Gross and Charles Lapiere in 1962, who observed enzymatic activity ( collagen triple helix degradation) during tadpole tail metamorphosis (by placing

301-635: A process known as angiogenesis . This process is essential for tumor progression, because as tumors grow they need increasing supplies of oxygen and nutrients. Localized MMP-2 activity plays an important role in endothelial cell migration, a key feature of angiogenesis . Additionally, MMP-9 and other MMPs have been suggested to also play a complex, indirect role in angiogenesis by promoting VEGF mobilization and generating antiangiogenic factors. For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that

344-438: A role in maintaining tissue homeostasis and preventing tumor progression. However, genetically unstable cancer cells can often evade regulation by TGF-β by altering TGF-β receptors in downstream signaling processes. Furthermore, expression of TGF-β is also correlated with immune tolerance and may help shield cancer cells from immune regulation. MMP-2 also plays an important role in the formation of new blood vessels within tumors,

387-430: A tadpole tail in a collagen matrix plate). Therefore, the enzyme was named interstitial collagenase ( MMP-1 ). Later, it was purified from human skin (1968), and was recognized to be synthesized as a zymogen . The "cysteine switch" was described in 1990. The MMPs have a common domain structure . The three common domains are the pro-peptide, the catalytic domain , and the haemopexin -like C-terminal domain, which

430-648: Is an enzyme that in humans is encoded by the MMP2 gene . The MMP2 gene is located on chromosome 16 at position 12.2. Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix (ECM) in normal physiological processes, such as embryonic development , reproduction , and tissue remodeling, as well as in disease processes, such as arthritis and metastasis . Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases . This gene encodes an enzyme which degrades type IV collagen ,

473-517: Is an oblate sphere measuring 35 x 30 x 30 Å (3.5 × 3 x 3 nm ). The active site is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site there is a catalytically important Zn ion, which is bound by three histidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif. The gelatinases , such as MMP-2 , incorporate Fibronectin type II modules inserted immediately before in

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516-435: Is coordinated to the protein via three ligands . The ligands coordinating the metal ion can vary with histidine , glutamate , aspartate , lysine , and arginine . The fourth coordination position is taken up by a labile water molecule. Treatment with chelating agents such as EDTA leads to complete inactivation. EDTA is a metal chelator that removes zinc, which is essential for activity. They are also inhibited by

559-519: Is difficult for researchers to determine whether the inhibitors have successfully reached their targets. However, initial clinical trials using broad spectrum MMP inhibitors did show some positive results. Phase I clinical trials showed that MMP inhibitors are generally safe with minimal adverse side effects. Additionally, trials with marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer. Various research groups have already suggested many strategies for improving

602-415: Is linked to the catalytic domain by a flexible hinge region. The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of the "cysteine switch." This contains a conserved cysteine residue that interacts with the zinc in the active site and prevents binding and cleavage of the substrate , keeping

645-628: Is often excessive in tumor environments and can provide a route of metastasis for cancer cells. Detry, et al. showed that knocking down mmp2 in zebrafish prevented the formation of lymphatic vessels without altering angiogenesis, while MMP-2 inhibition slowed the migration of lymphatic endothelial cells and altered the morphology of new vessels. These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis. Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to

688-433: Is their role in ECM degradation, which allows cancer cells to migrate out of the primary tumor to form metastases. More specifically, MMP-2 (along with MMP-9 ) is capable of degrading type IV collagen , the most abundant component of the basement membrane . The basement membrane is important for maintaining tissue organization, providing structural support for cells, and influencing cell signaling and polarity. Degradation of

731-588: Is thought to be involved in protein-protein interactions . This determines substrate specificity and is the site for interaction with TIMP's ( tissue inhibitor of metalloproteinases ). The hemopexin-like domain is absent in MMP-7 , MMP-23, MMP-26, and the plant and nematode . The membrane-bound MMPs (MT-MMPs) are anchored to the plasma membrane via a transmembrane or a GPI-anchoring domain. There are three catalytic mechanisms published. The MMPs can be subdivided in different ways. Use of bioinformatic methods to compare

774-1198: The endoplasmic reticulum and Golgi, binding one zinc ion per subunit. These endopeptidases include CAAX prenyl protease 1, which proteolytically removes the C-terminal three residues of farnesylated proteins . Metalloproteinase inhibitors are found in numerous marine organisms, including fish, cephalopods, mollusks, algae and bacteria. Members of the M50 metallopeptidase family include: mammalian sterol-regulatory element binding protein (SREBP) site 2 protease and Escherichia coli protease EcfE, stage IV sporulation protein FB. MMP2 1CK7 , 1CXW , 1EAK , 1GEN , 1GXD , 1HOV , 1J7M , 1KS0 , 1QIB , 1RTG , 3AYU 4313 17390 ENSG00000087245 ENSMUSG00000031740 P08253 P33434 NM_004530 NM_001127891 NM_001302508 NM_001302509 NM_001302510 NM_008610 NP_001121363 NP_001289437 NP_001289438 NP_001289439 NP_004521 NP_032636 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A

817-411: The zinc -binding motif in the catalytic domain. The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75 amino acids long, and has no determinable structure. The C-terminal domain has structural similarities to the serum protein hemopexin . It has a four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that

860-550: The ECM, MMPs release growth factors that were previously bound to the ECM, allowing them to bind with cell receptors and influence cell signaling. Furthermore, many MMPs also activate other proMMPs along with growth factors. MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as TGF-β , FGF receptor-1 , pro TNF , IL-1β and various chemokines . For instance, MMP-2 has been implicated, along with MMP-9 in cleaving latent TGF-β, which has complex interactions with cancer cells. TGF-β generally plays

903-468: The MMP2 gene cause a rare type of skeletal dysplasia Multicentric Osteolysis, Nodulosis, and Arthropathy syndrome. Abnormal mutations cause defective collagen remodelling. The disease manifestations include bone destruction especially of the wrists and tarsus, generalized osteoporosis and joint stiffness and eventually destruction. Altered expression and activity levels of MMPs have been strongly implicated in

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946-546: The activation of MMP-2 is cell-cell clustering. A wild-type activated leukocyte cell adhesion molecule ( ALCAM ) is also required to activate MMP-2. Mutations in the MMP2 gene are associated with Torg-Winchester syndrome , multicentric osteolysis , arthritis syndrome, and possibly keloids. Activity of MMP-2 relative to the other gelatinase ( MMP-9 ) has been associated with severity of chronic airway diseases including Idiopathic interstitial pneumonia and Bronchiectasis . In idiopathic interstitial pneumonia, MMP-2 activity

989-657: The basement membrane is an essential step for the metastatic progression of most cancers. Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of invadopodia , protrusive and adhesive structures on cancer cells. Invadopodia have been shown to concentrate MMPs (including MT1-MMP , MMP-2, and MMP-9) for localized release and activation. Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity. Finally, MMP-2 and several other MMPs have been shown to proteolytically activate TGF-β , which has been shown to promote epithelial mesenchymal transition (EMT),

1032-434: The case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule . In many instances, the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retained its function in protein recognition and binding . Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. In these enzymes,

1075-626: The case of trocade, promising results in rabbit arthritis models were not replicated in human trials). The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal models . Synergistic effect of stromelysin-1 (matrix metalloproteinase-3) promoter (-1171 5A->6A) polymorphism in oral submucous fibrosis and head and neck lesions.Chaudhary AK, Singh M, Bharti AC, Singh M, Shukla S, Singh AK, Mehrotra R. BMC Cancer. 2010 Jul 14;10:369. Metalloproteinase Most metalloproteases require zinc , but some use cobalt . The metal ion

1118-556: The chelator orthophenanthroline . There are two subgroups of metalloproteinases: In the MEROPS database peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine ; G, glutamic acid; M, metallo; S, serine ; T, threonine ; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases . In

1161-475: The effectiveness of MMP inhibitors in cancer treatment. First, highly specific MMP inhibitors could be used to target the functions of specific MMPs, which should allow doctors to increase the treatment dosage while minimizing adverse side effects. MMP inhibitors could also be administered along with cytotoxic agents or other proteinase inhibitors. Finally, MMP inhibitors could be used during earlier stages of cancer to prevent invasion and metastasis. Additionally,

1204-474: The enzyme in an inactive form. In the majority of the MMPs, the cysteine residue is in the conserved sequence PRCGxPD. Some MMPs have a prohormone convertase cleavage site (Furin-like) as part of this domain, which, when cleaved, activates the enzyme. MMP-23A and MMP-23B include a transmembrane segment in this domain. X-ray crystallographic structures of several MMP catalytic domains have shown that this domain

1247-451: The fact that MMPs play complex roles in tissue formation and cancer progression, and indeed many MMPs have both pro and anti-tumorogenic properties. Furthermore, most clinical studies involve advanced stages of cancer, where MMP inhibitors are not particularly effective. Finally, there are no reliable biomarkers available for assessing the efficacy of MMP inhibitors and MMPs are not directly cytotoxic (so they do not cause tumor shrinkage), so it

1290-576: The major structural component of basement membranes . The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response. Activation of MMP-2 requires proteolytic processing. A complex of membrane type 1 MMP (MT1-MMP/MMP14) and tissue inhibitor of metalloproteinase 2 recruits pro-MMP 2 from the extracellular milieu to the cell surface. Activation then requires an active molecule of MT1-MMP and auto catalytic cleavage. Clustering of integrin chains promotes activation of MMP-2. Another factor that will support

1333-493: The metal binding protein, metallothionine; thus helping in metal binding mechanism. The MMPs play an important role in tissue remodeling associated with various physiological or pathological processes such as morphogenesis , angiogenesis , tissue repair , cirrhosis , arthritis , and metastasis . MMP-2 and MMP-9 are thought to be important in metastasis. MMP-1 is thought to be important in rheumatoid arthritis and osteoarthritis. Recent data suggests active role of MMPs in

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1376-591: The metal-binding site. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin , 'b' is an uncharged residue, and 'c' a hydrophobic residue . Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases. Metallopeptidases from family M48 are integral membrane proteins associated with

1419-497: The overexpression of MMPs in tumors can potentially be leveraged to direct the release of chemotherapeutic agents specifically to tumor sites. For example, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that become activated only upon proteolytic cleavage by a target MMP. Moreover, the tumor-targeting characteristics of MMP inhibitors provide a promising strategy for identifying small tumors. Researchers could link MMP inhibitors to imaging agents to facilitate

1462-583: The pathogenesis of Aortic Aneurysm. Excess MMPs degrade the structural proteins of the aortic wall. Disregulation of the balance between MMPs and TIMPs is also a characteristic of acute and chronic cardiovascular diseases. All MMPs are synthesized in the latent form (Zymogen). They are secreted as proenzymes and require extracellular activation. They can be activated in vitro by many mechanisms including organomercurials, chaotropic agents, and other proteases. The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise

1505-478: The primary sequences of the MMPs suggest the following evolutionary groupings of the MMPs: Analysis of the catalytic domains in isolation suggests that the catalytic domains evolved further once the major groups had differentiated, as is also indicated by the substrate specificities of the enzymes . The most commonly used groupings (by researchers in MMP biology) are based partly on historical assessment of

1548-534: The progression and metastasis of many forms of cancer. Increased MMP-2 activity has also been linked with a poor prognosis in multiple forms of cancer including colorectal , melanoma , breast , lung , ovarian , and prostate . Furthermore, changes in MMP-2 activity can come from alterations in levels of transcription , MMP secretion, MMP activation, or MMP inhibition. MMP production in many cancers may be upregulated in surrounding stromal tissue rather than simply in

1591-412: The substrate specificity of the MMP and partly on the cellular localization of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane-type MMPs (MT-MMPs). However, it is becoming increasingly clear that these divisions are somewhat artificial as there are a number of MMPs that do not fit into any of the traditional groups. Matrix metalloproteinases combines with

1634-483: The treatment of periodontal disease and is the only MMP inhibitor that is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex . Minocycline, another tetracycline antibiotic, has also been shown to inhibit MMP activity. A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies that MMPs are suspected to be involved in (see above). However, most of these, such as marimastat (BB-2516),

1677-429: The tumor lesion. For instance, Mook, et al. showed that MMP-2 mRNA levels are strikingly similar between metastatic and non-metastatic lesions in colorectal cancer, but metastatic cases are correlated with higher levels of MMP-2 mRNA in surrounding healthy tissue. For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression. One of the major implications of MMPs in cancer progression

1720-549: The upregulation of these MMPs triggered the release of bioactive VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice. Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases. Finally, MMP-2 has been also shown to drive lymphangiogenesis , which

1763-412: The zinc atom. Other substituents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs. Doxycycline , at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions. It is used clinically for

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1806-430: The α v β 3 integrin expressed by human melanoma cells. Signaling through this integrin is necessary for melanoma cell viability and growth in a collagen matrix and can potentially rescue the cells from apoptosis . As another example, cleavage of laminin-5, a component of the basement membrane, by MMP-2 has been shown to reveal a cryptic site inducing migration of breast epithelial cells. More generally, by degrading

1849-453: Was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy. In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with Haemophilus influenzae airway infection compared to Pseudomonas aeruginosa airway infection. Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function. Disease-causing mutations in

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