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72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the ''MMP2''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. The ''MMP2'' gene is located on chromosome 16 at position 12.2.


Function

Proteins of the
matrix metalloproteinase 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 be ...
(MMP) family are involved in the breakdown of
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
(ECM) in normal physiological processes, such as
embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
,
reproduction Reproduction (or procreation or breeding) is the biological process by which new individual organisms – " offspring" – are produced from their "parent" or parents. Reproduction is a fundamental feature of all known life; each individual o ...
, and tissue remodeling, as well as in disease processes, such as
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some ...
and
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular
proteinase A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s. This gene encodes an enzyme which degrades type IV collagen, the major structural component of
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tissues including mesothelium and ...
s. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response.


Activation

Activation of MMP-2 requires
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases ...
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 Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
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 Torg-Winchester syndrome, multicentric
osteolysis Osteolysis is an active resorption of bone matrix by osteoclasts and can be interpreted as the reverse of ossification. Although osteoclasts are active during the natural formation of healthy bone the term "osteolysis" specifically refers to a path ...
,
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some ...
syndrome, and possibly keloids.


Role of MMP-2 in chronic disease

Activity of MMP-2 relative to the other
gelatinase Gelatinases are enzymes capable of degrading gelatin. Gelatinases are expressed in several bacteria including ''Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic– facultatively anaerobic, ro ...
( MMP-9) has been associated with severity of chronic airway diseases including
Idiopathic interstitial pneumonia Idiopathic interstitial pneumonia (IIP), or noninfectious pneumonia are a class of diffuse lung diseases. These diseases typically affect the pulmonary interstitium, although some also have a component affecting the airways (for instance, cryptog ...
and
Bronchiectasis Bronchiectasis is a disease in which there is permanent enlargement of parts of the airways of the lung. Symptoms typically include a chronic cough with mucus production. Other symptoms include shortness of breath, coughing up blood, and chest ...
. 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. In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with
Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacte ...
airway infection compared to
Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic– facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aer ...
airway infection. Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function. Disease-causing mutations in 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 the progression and
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
of many forms of cancer. Increased MMP-2 activity has also been linked with a poor
prognosis Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
in multiple forms of cancer including
colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being rem ...
, melanoma,
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and s ...
, lung, ovarian, and
prostate The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...
. 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 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.


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 Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also ...
, the most abundant component of the
basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tissues including mesothelium and ...
. 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. Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of
invadopodia Invadopodia are actin-rich protrusions of the plasma membrane that are associated with degradation of the extracellular matrix in cancer invasiveness and metastasis. Very similar to podosomes, invadopodia are found in invasive cancer cells and are ...
, 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 Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
, which has been shown to promote epithelial mesenchymal transition (EMT), a key process involved in cancer metastasis.


Role in cell signaling

MMP degradation of the ECM affects cellular behavior through changes in
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
-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 Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers. It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endom ...
can reveal a previously inaccessible cryptic binding site that binds with the αvβ3 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 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 Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
, FGF receptor-1, pro TNF,
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
and various
chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...
. For instance, MMP-2 has been implicated, along with MMP-9 in cleaving latent
TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
, 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.


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 Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
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 the upregulation of these MMPs triggered the release of bioactive
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
, 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 is often excessive in tumor environments and can provide a route of
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
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.


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. 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 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, tumor overexpression of MMPs can be used to potentially target the release of chemotherapeutic agents specifically to tumor sites. For instance, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that only become activated upon proteolytic cleavage by a target MMP. Finally, the tumor-targeting properties of MMP inhibitors offer a potential strategy for identifying small tumors. Researchers could couple MMP inhibitors to imaging agents to help detect 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.


Interactions

MMP2 has been shown to interact with: * CCL7, * THBS2, * TIMP2, * TIMP4, and * Thrombospondin 1.


References


Further reading

* * * *


External links

* The
MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibi ...
online database for peptidases and their inhibitors
M10.003
{{Use dmy dates, date=April 2017 Matrix metalloproteinases EC 3.4.24