MMP2: Difference between revisions

'''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 = 25228-3225228–32 | date = December 1992 | pmid = 1460022 | doi = }}</ref>

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 = 261-5261–5 | date = July 2001 | pmid = 11431697 | doi = 10.1038/90100 }}</ref> and possibly keloids.

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. 

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>

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_vβ₃ 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>

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.  

inhibitors have successfully reached their targets.<ref name=":0" />. 

patients with gastric or pancreatic cancer .<ref name=":0" />.  

for improving the effectiveness of MMP inhibitors in cancer treatment.   First, highly specific MMP inhibitors could be

cancer to prevent invasion and metastasis .<ref name=":0" />.  

of cancer cell invasion and metastasis .<ref name=":0" />.  

* [[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 = 1202-61202–6 | date = August 2000 | pmid = 10947989 | doi = 10.1126/science.289.5482.1202}}</ref>

* [[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 = 32167-7332167–73 | date = October 2000 | pmid = 10900205 | doi = 10.1074/jbc.M003834200 }}</ref>

* [[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 = 7414-97414–9 | date = May 2002 | pmid = 12032297 | pmc = 124245 | doi = 10.1073/pnas.102185399 }}</ref><ref name = "pmid10991943">{{vcite2 journal | vauthors = Overall CM, Tam E, McQuibban GA, Morrison C, Wallon UM, Bigg HF, King AE, Roberts CR | title = Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation | journal = J. Biol. Chem. | volume = 275 | issue = 50 | pages = 39497-50639497–506 | date = December 2000 | pmid = 10991943 | doi = 10.1074/jbc.M005932200 }}</ref><ref name = "pmid9182583">{{vcite2 journal | vauthors = Bigg HF, Shi YE, Liu YE, Steffensen B, Overall CM | title = Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2 | journal = J. Biol. Chem. | volume = 272 | issue = 24 | pages = 15496-50015496–500 | date = June 1997 | pmid = 9182583 | doi = 10.1074/jbc.272.24.15496}}</ref><ref name = "pmid12374789">{{vcite2 journal | vauthors = Kai HS, Butler GS, Morrison CJ, King AE, Pelman GR, Overall CM | title = Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain | journal = J. Biol. Chem. | volume = 277 | issue = 50 | pages = 48696-70748696–707 | date = December 2002 | pmid = 12374789 | doi = 10.1074/jbc.M209177200 }}</ref>

* {{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 = 1075-951075–95 | year = 1998 | pmid = 9737711 | doi = 10.1142/S0217984998001256 }}

* {{vcite2 journal | vauthors = Nagase H, Woessner JF | title = Matrix metalloproteinases | journal = J. Biol. Chem. | volume = 274 | issue = 31 | pages = 21491-421491–4 | year = 1999 | pmid = 10419448 | doi = 10.1074/jbc.274.31.21491 }}

* {{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 = 105-11105–11 | year = 2002 | pmid = 11961384 | doi = 10.1159/000053003 }}

* {{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 = 37-4537–45 | year = 2007 | pmid = 17718386 | doi = }}