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{{PBB|geneid=4313}}
'''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 =
== Function ==
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== Clinical significance ==
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 =
=== 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>
==== 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 [[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>
==== 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">{{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
==== Role in neovascularization and lymphangiogenesis ====
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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 ====
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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
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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 the effectiveness of MMP inhibitors in cancer treatment.
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, tumor overexpression of MMPs can be used to
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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
== Interactions ==
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MMP2 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CCL7]],<ref name = "pmid10947989">{{vcite2 journal | vauthors = McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I, Overall CM | title = Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 | journal = Science | volume = 289 | issue = 5482 | pages =
* [[THBS2]],<ref name = "pmid10900205">{{vcite2 journal | vauthors = Bein K, Simons M | title = Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity | journal = J. Biol. Chem. | volume = 275 | issue = 41 | pages =
* [[TIMP2]],<ref name = "pmid12032297">{{vcite2 journal | vauthors = Morgunova E, Tuuttila A, Bergmann U, Tryggvason K | title = Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 11 | pages =
* [[TIMP4]],<ref name = pmid9182583/><ref name = pmid12374789/> and
* [[Thrombospondin 1]].<ref name = pmid10900205/>
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== Further reading ==
{{refbegin|33em}}
* {{vcite2 journal | vauthors = Massova I, Kotra LP, Fridman R, Mobashery S | title = Matrix metalloproteinases: structures, evolution, and diversification | journal = FASEB J. | volume = 12 | issue = 12 | pages =
* {{vcite2 journal | vauthors = Nagase H, Woessner JF | title = Matrix metalloproteinases | journal = J. Biol. Chem. | volume = 274 | issue = 31 | pages =
* {{vcite2 journal | vauthors = Goffin F, Frankenne F, Béliard A, Perrier D'Hauterive S, Pignon MR, Geenen V, Foidart JM | title = Human endometrial epithelial cells modulate the activation of gelatinase a by stromal cells | journal = Gynecol. Obstet. Invest. | volume = 53 | issue = 2 | pages =
* {{vcite2 journal | vauthors = Hrabec E, Naduk J, Strek M, Hrabec Z | title = [Type IV collagenases (MMP-2 and MMP-9) and their substrates--intracellular proteins, hormones, cytokines, chemokines and their receptors] | journal = Postepy Biochem. | volume = 53 | issue = 1 | pages =
{{refend}}
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