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Literature summary for 3.4.24.24 extracted from
- Matrix metalloproteinase-2 not (just) a hero of the past (2019), Biochimie, 166, 223-232 .
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| tissue inhibitor of metalloproteinases-2 | TIMP-2, a physiological inhibitor of MMPs. proMMP-2 can be secreted either in a free form or already complexed with TIMP-2 through its C-terminal domain. In the first case, a TIMP-2 that inhibits a cell membrane-anchored MT1-MMP by interaction between its N-terminal inhibitory domain and the catalytic domain of MT1-MMP, acts as a binding site for free proMMP-2 by interaction between the proMMP-2 Hpx-like domain and the TIMP-2 C-terminal domain. ProMMP-2 present in the resulting MT1-MMP-TIMP-2-proMMP-2 complex can then be activated by another adjacent TIMP-2-free MT1-MMP. In the second case, the N-terminal inhibitory domain of TIMP-2 in the proMMP-2-TIMP-2 complex can interact with a cell membrane-anchored MT1-MMP. This proMMP-2 is then activated by an adjacent free MT1-MMP. To illustrate this process, it has been shown that proMMP-2 colocalizes with TIMP-2 and MT1-MMP inside caveolae on the surface of endothelial cells. Extracellular association of proMMP-2 and TIMP-2 depends on TIMP-2 phosphorylation by extracellular c-Src tyrosine kinase | Homo sapiens |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene MMP2, the gene is located on the long arm of chromosome 16 at position q12.2, the cDNA for MMP-2 codes for a 660 residues preproenzyme containing a 29 residues signal peptide responsible for translocation to the endoplasmic reticulum and followed by the 72-kDa-proenzyme. The human MMP2 gene lacks a conventional TATA-box or classical transcription response elements found in other MMP genes, the constitutive expression depends on p53-, Sp1-, Sp3-and AP-2-binding sites but the promoter contains other cis-regulatory elements including C/EBP, ATF2, PEA3/Ets, c-myc and AP-1 binding sites. Transcriptionally active MMP-2 in invasive cancer cells is characterized by hypomethylation of CpG regions in the MMP2 promoter and low levels of histone H3 lysine-27 trimethylation | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| alpha2-Macroglobulin | - |
Homo sapiens | |
| additional information | while TIMP-2, TIMP-3 and TIMP-4 are able to strongly interact with proMMP-2, TIMP-2 is the only one contributing to cell-surface activation of the proenzyme by MT1-MMP. Such antagonistic properties of TIMP-2 (inhibition vs. activation) highlight its seminal role in the control of pericellular MMP-2 activity | Homo sapiens | |
| netrin | - |
Homo sapiens | |
| procollagen C-terminal proteinase enhancer | PCPE | Homo sapiens | |
| RECK | reversion-inducing cysteine-rich protein with Kazal motifs | Homo sapiens | |
| TIMP-1 | binding also involves interaction between TIMP and the MMP-2 Hpx-like domain | Homo sapiens | |
| TIMP-3 | binding also involves interaction between TIMP and the MMP-2 Hpx-like domain | Homo sapiens | |
| TIMP-4 | binding also involves interaction between TIMP and the MMP-2 Hpx-like domain | Homo sapiens | |
| tissue factor pathway inhibitor | TFPI-2 | Homo sapiens | |
| tissue inhibitor of metalloproteinases-2 | TIMP-2, a physiological inhibitor of MMPs. proMMP-2 can be secreted either in a free form or already complexed with TIMP-2 through its C-terminal domain. In the first case, a TIMP-2 that inhibits a cell membrane-anchored MT1-MMP by interaction between its N-terminal inhibitory domain and the catalytic domain of MT1-MMP, acts as a binding site for free proMMP-2 by interaction between the proMMP-2 Hpx-like domain and the TIMP-2 C-terminal domain. ProMMP-2 present in the resulting MT1-MMP-TIMP-2-proMMP-2 complex can then be activated by another adjacent TIMP-2-free MT1-MMP. In the second case, the N-terminal inhibitory domain of TIMP-2 in the proMMP-2-TIMP-2 complex can interact with a cell membrane-anchored MT1-MMP. This proMMP-2 is then activated by an adjacent free MT1-MMP. To illustrate this process, it has been shown that proMMP-2 colocalizes with TIMP-2 and MT1-MMP inside caveolae on the surface of endothelial cells. Extracellular association of proMMP-2 and TIMP-2 depends on TIMP-2 phosphorylation by extracellular c-Src tyrosine kinase | Homo sapiens |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cell surface | besides MT-MMPs, which efficiently bind proMMP-2 to induce its activation, a limited number of cell-surface molecules have been shown to contribute to enhance proteolytic activity at the migrating front of invasive cells by clustering active MMP-2 at the cell membrane. Among them the heat shock protein HSP90a expressed at the surface of tumor cells promotes MMP-2 activity and tumor invasion by binding to the Hpx-like domain of MMP-2. The alphanybeta3 integrin is first identified as a binding site for the C-terminal Hpx-like domain of MMP-2 in studies investigating in vivo and in vitro interactions between angiogenic blood vessels and melanoma cells | Homo sapiens | 9986 | - |
| cytosol | - |
Homo sapiens | 5829 | - |
| endoplasmic reticulum | - |
Homo sapiens | 5783 | - |
| extracellular | the enzyme is secreted. proMMP-2 can be secreted either in a free form or already complexed with TIMP-2 through its C-terminal domain. Extracellular association of proMMP-2 and TIMP-2 depends on TIMP-2 phosphorylation by extracellular c-Src tyrosine kinase | Homo sapiens | - |
- |
| Golgi apparatus | - |
Homo sapiens | 5794 | - |
| mitochondrion | - |
Homo sapiens | 5739 | - |
| additional information | the enzyme sequence contains a 29-residues-signal peptide responsible for translocation to the endoplasmic reticulum. Secreted enzyme MMP-2 can be endocytosed through direct or indirect binding to several membrane proteins, translocation across the endosome membrane towards the cytosol. Besides its transient journey in the secretory pathway (endoplasmic reticulum, Golgi apparatus and related vesicles), intracellular MMP-2 is not restricted to the cytosol but is also found in organelles including nucleus and mitochondria. proMMP-2 can be secreted either in a free form or already complexed with TIMP-2 through its C-terminal domain. LRP-2 is able to bind and endocytose proMMP-2 complexed to TIMP-2 | Homo sapiens | - |
- |
| nucleus | - |
Homo sapiens | 5634 | - |
| vesicle | - |
Homo sapiens | 31982 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | required | Homo sapiens |  |
| Zn2+ | zinc metalloproteinase, the Zn2+-binding motif of the catalytic domain is preceded by three cysteine-rich repeats comparable to the collagen-binding fibronectin type II (FN-II) repeats, which are required for recognizing collagen and elastin | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| Collagen + H2O | Homo sapiens | - |
? | - |
? | |
| Gelatin + H2O | Homo sapiens | - |
? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P08253 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| proteolytic modification | the enzyme is secreted as an inactive pro-MMP and proteolytically activated to mature MMP-2. ProMMP-2 is composed of a propeptide followed by a catalytic domain that is connected to a hemopexin (Hpx)-like domain through a linker sequence. A free zinc-ligating thiol group present in the propeptide maintains the enzyme latency until activation (cysteine switch). The latent proform of most MMPs is generally processed in the extracellular compartment by proteolytic removal of the about 10-kDa. proMMP-2 cannot be fully activated by most extracellular proteinases. For example, thrombin alone is unable to fully activate proMMP-2 and activation of proMMP-2 by neutrophil elastase, cathepsin G or proteinase-3 depends on the expression of membrane-type 1 MMP (MT1-MMP). A prominent mechanism for proMMP-2 activation occurs at the cell surface and depends on the MT-MMPs, mainly MT1-MMP. The six MT-MMPs are associated to cell membranes by either a type I transmembrane domain (MT1-, MT2-, MT3-and MT5-MMPs) or a glycosylphosphatidylinositol (GPI) anchor (MT4- and MT6-MMPs). Their pericellular activities are diverse and include ECM degradation and shedding and activation processes. Only MT4-MMP does not activate proMMP-2. The recombinant catalytic domain of MT5-MMP generates the active form of MMP-2. Activation of proMMP-2 by MT3-MMP requires a preliminary interaction between chondroitin sulfate glycosaminoglycans expressed at the cell surface and the Hpx-like domain of proMMP-2. MT2-MMP activates proMMP-2 by directly interacting with the Hpx-like domain of the proenzyme. Mechanisms of proMMP-2 activation by MT1-MMP involve tissue inhibitor of metalloproteinases-2 (TIMP-2), a physiological inhibitor of MMPs | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| blood plasma | - |
Homo sapiens | - |
| blood vessel | - |
Homo sapiens | - |
| carcinoma cell | the enzyme is overexpressed in tumors, it is expressed in all tumors tested | Homo sapiens | - |
| colon | - |
Homo sapiens | - |
| endothelial cell | - |
Homo sapiens | - |
| glioblastoma cell | - |
Homo sapiens | - |
| heart | - |
Homo sapiens | - |
| kidney | - |
Homo sapiens | - |
| lung | - |
Homo sapiens | - |
| melanoma cell | - |
Homo sapiens | - |
| mesenchyme | - |
Homo sapiens | - |
| placenta | - |
Homo sapiens | - |
| prostate gland | - |
Homo sapiens | - |
| smooth muscle | - |
Homo sapiens | - |
| testis | - |
Homo sapiens | - |
| urinary bladder | - |
Homo sapiens | - |
| uterine cervix | - |
Homo sapiens | - |
| uterine endometrium | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| Collagen + H2O | - |
Homo sapiens | ? | - |
? | |
| Gelatin + H2O | - |
Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 72000 | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| gelatinase A | - |
Homo sapiens |
| matrix metalloproteinase-2 | - |
Homo sapiens |
| MMP-2 | - |
Homo sapiens |
| Type IV collagenase | - |
Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | MMP-2 is a member of the matrix metalloproteinase family | Homo sapiens |
| additional information | the Zn2+-binding motif of the catalytic domain is preceded by three cysteine-rich repeats comparable to the collagen-binding fibronectin type II (FN-II) repeats, which are required for recognizing collagen and elastin | Homo sapiens |
| physiological function | matrix metalloproteinase MMP-2 degrades components of the extracellular matrix, denatured interstitial type I collagen and native type IV collagen. MMP-2 is a key player in cancer invasion and metastasis. Different mechanisms contribute to regulate the activity of MMP-2 during its molecular existence: expression, secretion, activation, extra/pericellular localization, inhibition, endocytosis and lysosomal degradation. Epigenetic control also contributes to MMP-2 regulation. Levels of control of extra/pericellular MMP-2, overview The enzyme is present in the extracellular compartment for degrading denatured type I collagen. Cell membrane-bound MMP-2 can also act as transducers and trigger outside-in signaling. Binding of proMMP-2 to alphavbeta3 integrin on the surface of lung cancer cells stimulates tumor angiogenesis by activating PI3K/AKT pathway and HIF-1alpha, leading to VEGF-A expression | Homo sapiens |
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