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{{Short description|Protein-coding gene in humans}}
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'''72 kDa type IV collagenase''' also known as '''matrix metalloproteinase-2''' (MMP-2) and '''gelatinase A''' is an [[enzyme]] that in humans is encoded by the ''MMP2'' [[gene]].<ref name="pmid1460022">{{vcite2 journal | vauthors = Devarajan P, Johnston JJ, Ginsberg SS, Van Wart HE, Berliner N | title = Structure and expression of neutrophil gelatinase cDNA. Identity with type IV collagenase from HT1080 cells | journal = J. Biol. Chem. | volume = 267 | issue = 35 | pages = 25228-32 | date = December 1992 | pmid = 1460022 | doi = }}</ref>▼
{{Infobox gene}}
▲'''72 kDa type IV collagenase''' also known as '''matrix metalloproteinase-2''' (MMP-2) and '''gelatinase A''' is an [[enzyme]] that in humans is encoded by the ''MMP2'' [[gene]].<ref name="pmid1460022">{{
== Function ==
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 [[proprotein]]s which are activated when cleaved by extracellular [[proteinase]]s. This gene encodes an enzyme which degrades type IV [[collagen]], the major structural component of [[basement membrane]]s. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response.<ref>{{cite web | title = Entrez Gene: MMP2 matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)| url =
▲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 [[proprotein]]s which are activated when cleaved by extracellular [[proteinase]]s. This gene encodes an enzyme which degrades type IV [[collagen]], the major structural component of [[basement membrane]]s. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response.<ref>{{cite web | title = Entrez Gene: MMP2 matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4313| accessdate = }}</ref>
== Activation ==
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 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.
== Clinical significance ==
Mutations in the MMP2 gene are associated with [[Winchester syndrome|Torg-Winchester syndrome]], multicentric [[osteolysis]], [[arthritis]] syndrome,<ref name="pmid11431697">{{
▲Mutations in the MMP2 gene are associated with [[Winchester syndrome|Torg-Winchester syndrome]], multicentric [[osteolysis]], [[arthritis]] syndrome,<ref name="pmid11431697">{{vcite2 journal | vauthors = Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ | title = Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome | journal = Nat. Genet. | volume = 28 | issue = 3 | pages = 261-5 | date = July 2001 | pmid = 11431697 | doi = 10.1038/90100 }}</ref> 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 was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy.<ref name="pmid11069839">{{cite journal | vauthors = Suga M, Iyonaga K, Okamoto T, Gushima Y, Miyakawa H, Akaike T, Ando M | title = Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias | journal = American Journal of Respiratory and Critical Care Medicine | volume = 162 | issue = 5 | pages = 1949–56 | date = November 2000 | pmid = 11069839 | doi = 10.1164/ajrccm.162.5.9906096 }}</ref> In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with [[Haemophilus influenzae|''Haemophilus influenzae'']] airway infection compared to [[Pseudomonas aeruginosa|''Pseudomonas aeruginosa'']] airway infection.<ref name="pmid25679336">{{cite journal | vauthors = Taylor SL, Rogers GB, Chen AC, Burr LD, McGuckin MA, Serisier DJ | title = Matrix metalloproteinases vary with airway microbiota composition and lung function in non-cystic fibrosis bronchiectasis | journal = Annals of the American Thoracic Society | volume = 12 | issue = 5 | pages = 701–7 | date = May 2015 | pmid = 25679336 | doi = 10.1513/AnnalsATS.201411-513OC }}</ref> Bronchiectasis patients with ''P. aeruginosa'' infection have a more rapid decline in lung function.<ref name="pmid24592925">{{cite journal | vauthors = Rogers GB, Zain NM, Bruce KD, Burr LD, Chen AC, Rivett DW, McGuckin MA, Serisier DJ | title = A novel microbiota stratification system predicts future exacerbations in bronchiectasis | journal = Annals of the American Thoracic Society | volume = 11 | issue = 4 | pages = 496–503 | date = May 2014 | pmid = 24592925 | doi = 10.1513/AnnalsATS.201310-335OC }}</ref> Disease-causing mutations in the MMP2 gene cause a rare type of skeletal dysplasia [[Winchester syndrome|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.<ref>{{cite journal | vauthors = Bhavani GS, Shah H, Shukla A, Gupta N, Gowrishankar K, Rao AP, Kabra M, Agarwal M, Ranganath P, Ekbote AV, Phadke SR, Kamath A, Dalal A, Girisha KM | title = Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy | journal = American Journal of Medical Genetics. Part A | volume = 170A | issue = 2 | pages = 410–417 | date = February 2016 | pmid = 26601801 | doi = 10.1002/ajmg.a.37447 | doi-access = free }}</ref><ref name=Elsebaie/>
Altered expression and activity levels of MMPs have been strongly implicated in 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 cancer|colorectal]], [[melanoma]], [[breast cancer|breast]], [[lung cancer|lung]], [[Ovarian cancer|ovarian]], and [[prostate cancer|prostate]].<ref name=":0">{{
▲=== Role of MMP-2 in cancer progression ===
▲Altered expression and activity levels of MMPs have been strongly implicated in 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 cancer|colorectal]], [[melanoma]], [[breast cancer|breast]], [[lung cancer|lung]], [[Ovarian cancer|ovarian]], and [[prostate cancer|prostate]]<ref name=":0">{{vcite2 journal | vauthors = Björklund M, Koivunen E | title = Gelatinase-mediated migration and invasion of cancer cells | journal = Biochimica et Biophysica Acta | volume = 1755 | issue = 1 | pages = 37–69 | date = May 2005 | pmid = 15907591 | doi = 10.1016/j.bbcan.2005.03.001 }}</ref>. 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 [[Stroma (animal tissue)|stromal tissue]] rather than simply in 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<ref name="Mook_2004">{{vcite2 journal | vauthors = Mook OR, Frederiks WM, Van Noorden CJ | title = The role of gelatinases in colorectal cancer progression and metastasis | journal = Biochimica et Biophysica Acta | volume = 1705 | issue = 2 | pages = 69–89 | date = Dec 2004 | pmid = 15588763 | doi = 10.1016/j.bbcan.2004.09.006 }}</ref>. For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression.
==== Role in cancer cell invasion ====
One of the major implications of MMPs in cancer progression 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 the basement membrane is an essential step for the metastatic progression of most cancers.<ref name="Mook_2004" />
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
▲One of the major implications of MMPs in cancer progression 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 the basement membrane is an essential step for the metastatic progression of most cancers<ref name="Mook_2004" />.
▲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<ref>{{vcite2 journal | vauthors = Jacob A, Prekeris R | title = The regulation of MMP targeting to invadopodia during cancer metastasis | journal = Frontiers in Cell and Developmental Biology | volume = 3 | pages = 4 | pmid = 25699257 | doi = 10.3389/fcell.2015.00004 }}</ref>. Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity<ref>{{vcite2 journal | vauthors = Clark ES, Whigham AS, Yarbrough WG, Weaver AM | title = Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4227–35 | date = May 2007 | pmid = 17483334 | doi = 10.1158/0008-5472.CAN-06-3928 }}</ref>. 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), a key process involved in cancer metastasis.<ref>{{vcite2 journal | vauthors = Gialeli C, Theocharis AD, Karamanos NK | title = Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting | journal = The FEBS Journal | volume = 278 | issue = 1 | pages = 16–27 | date = Jan 2011 | pmid = 21087457 | doi = 10.1111/j.1742-4658.2010.07919.x }}</ref>
==== Role in cell signaling ====
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.<ref name="McCawley_2000">{{
More generally, by degrading 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
▲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.<ref name="McCawley_2000">{{vcite2 journal | vauthors = McCawley LJ, Matrisian LM | title = Matrix metalloproteinases: multifunctional contributors to tumor progression | journal = Molecular Medicine Today | volume = 6 | issue = 4 | pages = 149–56 | date = Apr 2000 | pmid = 10740253 }}</ref> For instance, MMP-2 degradation of [[collagen type I]] can reveal a previously inaccessible cryptic binding site that binds with the α<sub>v</sub>β<sub>3</sub> 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]].<ref>{{vcite2 journal | vauthors = Montgomery AM, Reisfeld RA, Cheresh DA | title = Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 19 | pages = 8856–60 | date = Sep 1994 | pmid = 7522323 }}</ref> 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<ref>{{vcite2 journal | vauthors = Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V | title = Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5 | journal = Science | volume = 277 | issue = 5323 | pages = 225–28 | date = Jul 1997 | pmid = 9211848 }}</ref>.
▲More generally, by degrading 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.<ref name="McCawley_2000" /> MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as [[TGF-β]], [[Fibroblast growth factor receptor|FGF receptor-1]], pro[[Tumor necrosis factor alpha|TNF]], [[IL-1β]] and various [[chemokines]].<ref>{{vcite2 journal | vauthors = Detry B, Erpicum C, Paupert J, Blacher S, Maillard C, Bruyère F, Pendeville H, Remacle T, Lambert V, Balsat C, Ormenese S, Lamaye F, Janssens E, Moons L, Cataldo D, Kridelka F, Carmeliet P, Thiry M, Foidart JM, Struman I, Noël A | title = Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase | journal = Blood | volume = 119 | issue = 21 | pages = 5048–56 | date = May 2012 | pmid = 22490679 | doi = 10.1182/blood-2011-12-400267 }}</ref> 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 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.<ref>{{vcite2 journal | vauthors = Massagué J | title = TGFbeta in Cancer | journal = Cell | volume = 134 | issue = 2 | pages = 215–30 | date = Jul 2008 | pmid = 18662538 | doi = 10.1016/j.cell.2008.07.001 }}</ref>
==== Role in neovascularization and lymphangiogenesis ====
MMP-2 also plays an important role in the formation of new blood vessels within tumors, 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.<ref name="Mook_2004" />
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 the upregulation of these MMPs triggered the release of bioactive
Finally, MMP-2 has been also shown to drive [[lymphangiogenesis]], which 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.<ref name="Mook_2004" /> These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis.
==== Inhibition of MMP-2 as cancer therapy ====
Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to 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 is difficult for researchers to determine whether the inhibitors have successfully reached their targets.<ref name=":0" />
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.<ref name=":0" />
Various research groups have already suggested many strategies for improving 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.<ref name=":0" />
Additionally, 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 the detection of tumors before they spread. Though initial trials yielded disappointing results, MMP inhibitors offer significant potential for improving cancer treatment by slowing the process of cancer cell invasion and metastasis.<ref name=":0" />
== Interactions ==
MMP2 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CCL7]],<ref name = "pmid10947989">{{
* [[THBS2]],<ref name = "pmid10900205">{{
* [[TIMP2]],<ref name = "pmid12032297">{{
* [[TIMP4]],<ref name = pmid9182583/><ref name = pmid12374789/> and
* [[Thrombospondin 1]].<ref name = pmid10900205/>
{{Div col end}}
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== Further reading ==
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{{PDB Gallery|geneid=4313}}
{{Metalloendopeptidases}}
{{Enzymes}}
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{{Use dmy dates|date=April 2017}}
[[Category:
[[Category:EC 3.4.24]]
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