MMP15 (matrix metallopeptidase 15 (membrane-inserted))
2012-10-01 Emiko Ito , Ikuo Yana , Nariaki Matsuura AffiliationDepartment of Molecular Pathology, Graduate School of Medicine, Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Identity
HGNC
LOCATION
16q21
LOCUSID
ALIAS
MMP-15,MT2-MMP,MT2MMP,MTMMP2,SMCP-2
FUSION GENES
DNA/RNA
Description
This gene can be found on chromosome16 at location: 58028573-58163296.
Transcription
The DNA sequence contains 10 exons and the transcript length: 3530 bp translated to a 699 residues protein.
Proteins
Description
MT2-MMP belongs to which consist a gene family over 25 different members in humans (refer to MT1-MMP).
Expression
Expression of MT2-MMP has been reported in many cancers, such as glioblastomas, ovarian, urothelial, and breast. In addition, MT2-MMP is involved in endothelial tubulogenesis, malignant conversion of keratinocytes, and is an antiapoptotic factor.
Both MT2-MMP and MT3-MMP were detected predominantly at the interface between the epithelium and substantia propia in mice intracornea infected with Pseudomonas aeruginosa. On the other hand, MT1-MMP was mainly expressed at epithelium in the same tissue (Dong et al., 2000). During pregnancy, MT2-MMP is expressed in the invaded cytotrophoblasts where both MT1-MMP and gelatinase A are extensively colocalized (Bjørn et al., 2000).
Over all, MT2-MMP may plays an important and distinct role from MT1-MMP in normal physiological processes.
Both MT2-MMP and MT3-MMP were detected predominantly at the interface between the epithelium and substantia propia in mice intracornea infected with Pseudomonas aeruginosa. On the other hand, MT1-MMP was mainly expressed at epithelium in the same tissue (Dong et al., 2000). During pregnancy, MT2-MMP is expressed in the invaded cytotrophoblasts where both MT1-MMP and gelatinase A are extensively colocalized (Bjørn et al., 2000).
Over all, MT2-MMP may plays an important and distinct role from MT1-MMP in normal physiological processes.
Localisation
Plasma membrane.
Function
In a previous study with a cell line established from MT1-MMP gene knocked-out mice, MT2-MMP has been suggested to contribute alternatively to cell invasion through fibrin rich matrices (Hotary et al., 2002).
Like as MT1-MMP, MT2-MMP may also play some role in MMP-2 activation in microenvironment with TIMP-2 involvement (Morrison et al., 2001; Morrison and Overall, 2006).
In corporation with the enzymatic action of MT1-MMP, MT2-MMP can contribute to remodel basement membrane (Hotary et al., 2000; Hotary et al., 2006).
Like as MT1-MMP, MT2-MMP may also play some role in MMP-2 activation in microenvironment with TIMP-2 involvement (Morrison et al., 2001; Morrison and Overall, 2006).
In corporation with the enzymatic action of MT1-MMP, MT2-MMP can contribute to remodel basement membrane (Hotary et al., 2000; Hotary et al., 2006).
Development
1) Branching morphogenesis
MT2-MMP has been shown to be induced to the epithelia in migration, thereby speculated to be involved in branching morphogenesis of salivery gland (Harunaga et al., 2011), and submandibular gland (Rebustini et al., 2009).
2) Cardia valve development in endocardial cushion
Cardiac valve is constituted by tissue-specific fibroblasts originated from endocardial cushion through EMT. It has been demonstrated that MT2-MMP, which may play a key role in the valve formation, is likely expressed at the period of EMT by Snail1-related signal (Tao et al., 2011).
3) Placenta development (chorionic villus)
It has been demonstrated by separate research groups that MT2-MMP may play a important role in placental labyrinth formation at the period of embryogenesis or in menstrual cycle (Szabova et al., 2010; Plaisier et al., 2006). During the placenta development, MT2-MMP is induced at trophoblasts under TNF alpha-related signal.
Homology
MT2-MMP is supposed to be 72 kDa in molecular weight with overall similarity to MT1-MMP by 73,9%.
Implicated in
Entity name
Cancer progression
Note
Both MT1-MMP and MT2-MMP have potential to play important role in cancer either for proliferation or transmigration through extracellular matrix (ECM). Ota and his colleagues have suggested that membrane-localized proteolytic enzyme such as MT1/2-MMP can be induced and recruited towards the tumor cell surface during epithelial-mesenchymal transition (EMT) mediated by Snail1-related signal (Ota et al., 2009). Other group has indicated that cancer cells, such as PANC-1, induce MT2-MMP under hypoxia in a HIF-1 dependent manner (Zhu et al., 2011). These data suggest MT2-MMP may play some role in cancer progression against the physiological stress. It has not been clarified, however, that MT2-MMP can entirely substitute the function of MT1-MMP and vice versa.
Several IHS analyses with clinical samples suggested that MT2-MMP is expressed in several tumor types which include esophageal (Chen et al., 2010), bladder (Mohammad et al., 2010), colorectal (Lyall et al., 2006), and urothelial carcinoma (Kitagawa et al., 1998). In such reports for the colorectal and bladder cancer, the expression of MT2-MMP was shown to be associated with disease prognosis (Lyall et al., 2006; Mohammad et al., 2010).
Several IHS analyses with clinical samples suggested that MT2-MMP is expressed in several tumor types which include esophageal (Chen et al., 2010), bladder (Mohammad et al., 2010), colorectal (Lyall et al., 2006), and urothelial carcinoma (Kitagawa et al., 1998). In such reports for the colorectal and bladder cancer, the expression of MT2-MMP was shown to be associated with disease prognosis (Lyall et al., 2006; Mohammad et al., 2010).
Entity name
Idiopathic pulmonary fibrosis (IPF)
Note
IPF is a disease characterized by fibroblast expansion and ECM accumulation in lung. A previous report suggests MT1-MMP as well as MT2-MMP, was expressed in alveolar epithelial cells, and active MMP-2 was increased in bronchoalveolar lavage (BAL) fluids in IPF tissue. These MMPs possibly play roles in the pathogeny (García-Alvarez et al., 2006).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16093241 | 2005 | Identification of MMP-15 as an anti-apoptotic factor in cancer cells. | Abraham R et al |
| 17543340 | 2008 | Prognostic values of matrix metalloproteinase family expression in human colorectal carcinoma. | Asano T et al |
| 16103082 | 2005 | PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression. | Bassi DE et al |
| 10736239 | 2000 | Messenger RNA for membrane-type 2 matrix metalloproteinase, MT2-MMP, is expressed in human placenta of first trimester. | Bjørn SF et al |
| 21036765 | 2010 | Immunochemical staining of MT2-MMP correlates positively to angiogenesis of human esophageal cancer. | Chen L et al |
| 15619017 | 2004 | Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the basis of expression of metastasis/invasion-related factors and p53. | Chiba H et al |
| 20803418 | 2011 | Crocetin inhibits invasiveness of MDA-MB-231 breast cancer cells via downregulation of matrix metalloproteinases. | Chryssanthi DG et al |
| 15623598 | 2004 | Matrix metalloproteinase/tissue inhibitors of matrix metalloproteinase phenotype identifies poor prognosis colorectal cancers. | Curran S et al |
| 12664060 | 2003 | Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines. | Daja MM et al |
| 11293899 | 2001 | Expression of membrane-type 1, 2, and 3 matrix metalloproteinases messenger RNA in ovarian carcinoma cells in serous effusions. | Davidson B et al |
| 17066518 | 2006 | Inflammatory gene expression patterns revealed by DNA microarray analysis in TNF-alpha-treated SGBS human adipocytes. | Do MS et al |
| 11095614 | 2000 | Membrane-type matrix metalloproteinases in mice intracorneally infected with Pseudomonas aeruginosa. | Dong Z et al |
| 10585576 | 2000 | Role of MT-MMPs and MMP-2 in pancreatic cancer progression. | Ellenrieder V et al |
| 16469749 | 2006 | Individual Timp deficiencies differentially impact pro-MMP-2 activation. | English JL et al |
| 12416653 | 2002 | Screening of novel matrix metalloproteinases (MMPs) in human fetal membranes. | Fortunato SJ et al |
| 16933466 | 2006 | Membrane type-matrix metalloproteinases in idiopathic pulmonary fibrosis. | García-Alvarez J et al |
| 12773401 | 2003 | Expression pattern of metalloproteinases and tissue inhibitors of matrix-metalloproteinases in cycling human endometrium. | Goffin F et al |
| 21487116 | 2011 | Dynamics of salivary gland morphogenesis. | Harunaga J et al |
| 18093301 | 2007 | The first trimester human trophoblast cell line ACH-3P: a novel tool to study autocrine/paracrine regulatory loops of human trophoblast subpopulations--TNF-alpha stimulates MMP15 expression. | Hiden U et al |
| 17724206 | 2007 | MMP and TIMP expression in quiescent, dividing, and differentiating human lens cells. | Hodgkinson LM et al |
| 10851027 | 2000 | Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. | Hotary K et al |
| 16983145 | 2006 | A cancer cell metalloprotease triad regulates the basement membrane transmigration program. | Hotary K et al |
| 11828004 | 2002 | Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. | Hotary KB et al |
| 14582707 | 2003 | A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. | Ishii Y et al |
| 20117087 | 2010 | The role of MT2-MMP in cancer progression. | Ito E et al |
| 11125539 | 2000 | Expression of matrix metalloproteinases and their inhibitors by rat NK cells: inhibition of their expression by genistein. | Kim MH et al |
| 9751409 | 1998 | Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human urothelial carcinomas. | Kitagawa Y et al |
| 14755238 | 2004 | Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo. | Kobayashi K et al |
| 9609663 | 1998 | Localization of the human membrane-type 2 matrix metalloproteinase gene (MMP15) to 16q12.1 near DNA elements that are part of centromeric and non-centromeric heterochromatin of 11 human chromosomes. | Koehler MR et al |
| 9088534 | 1997 | Activation of progelatinase A and progelatinase A/TIMP-2 complex by membrane type 2-matrix metalloproteinase. | Kolkenbrock H et al |
| 15754008 | 2005 | Genistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitors. | Kousidou OC et al |
| 15551360 | 2005 | Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13. | Lafleur MA et al |
| 17201186 | 2006 | Gonadotropin-releasing hormone analogues alter gene expression of metalloproteinases and their tissue inhibitors in human breast cancer epithelial cells. | Lamari FN et al |
| 9708803 | 1998 | Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. | Lampert K et al |
| 14505115 | 2003 | Proteases in brain tumour progression. | Levicar N et al |
| 16489072 | 2006 | Profiling markers of prognosis in colorectal cancer. | Lyall MS et al |
| 11960907 | 2002 | Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4. | Mahloogi H et al |
| 21167057 | 2010 | Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. | Mao L et al |
| 10656737 | 2000 | Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. | Matsui K et al |
| 9070935 | 1997 | Genes of the membrane-type matrix metalloproteinase (MT-MMP) gene family, MMP14, MMP15, and MMP16, localize to human chromosomes 14, 16, and 8, respectively. | Mattei MG et al |
| 10673371 | 2000 | Human membrane type-2 matrix metalloproteinase is defective in cell-associated activation of progelatinase A. | Miyamori H et al |
| 20586027 | 2010 | Prognostic value of membrane type 1 and 2 matrix metalloproteinase expression and gelatinase A activity in bladder cancer. | Mohammad MA et al |
| 16825197 | 2006 | TIMP independence of matrix metalloproteinase (MMP)-2 activation by membrane type 2 (MT2)-MMP is determined by contributions of both the MT2-MMP catalytic and hemopexin C domains. | Morrison CJ et al |
| 10027400 | 1999 | Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. | Nakada M et al |
| 12452868 | 2002 | Elevated expression of extracellular matrix metalloproteinase inducer (CD147) and membrane-type matrix metalloproteinases in venous leg ulcers. | Norgauer J et al |
| 15870919 | 2005 | Expression of matrix metalloproteinases (MMPs) in cultured hepatocellular carcinoma (HCC) cells and surgically resected HCC tissues. | Ogasawara S et al |
| 11858950 | 2002 | Immunohistochemical study of membrane type-matrix metalloproteinases (MT-MMPs) and matrix metalloproteinase-2 (MMP-2) in dermatofibroma and malignant fibrous histiocytoma. | Ohnishi Y et al |
| 11525948 | 2001 | Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells. | Ohnishi Y et al |
| 11217446 | 2000 | Tumor cell-matrix interaction: pericellular matrix degradation and metastasis. | Okada Y et al |
| 19915148 | 2009 | Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. | Ota I et al |
| 10857781 | 2000 | Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. | Pap T et al |
| 18854409 | 2009 | Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions. | Plaisier M et al |
| 22684036 | 2012 | Expression analysis of zebrafish membrane type-2 matrix metalloproteinases during embryonic development. | Quick RE et al |
| 17512973 | 2007 | VEGF increases the fibrinolytic activity of endothelial cells within fibrin matrices: involvement of VEGFR-2, tissue type plasminogen activator and matrix metalloproteinases. | Ratel D et al |
| 19853562 | 2009 | MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis. | Rebustini IT et al |
| 10936678 | 2000 | Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. | Sameshima T et al |
| 22010885 | 2012 | The effect of cyclic mechanical strain on the expression of adhesion-related genes by periodontal ligament cells in two-dimensional culture. | Saminathan A et al |
| 9198203 | 1997 | Membrane-type matrix metalloproteinases (MT-MMPs) in cell invasion. | Sato H et al |
| 17030988 | 2006 | Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. | Saunders WB et al |
| 9653660 | 1998 | Mapping of two mouse membrane-type matrix metalloproteinase (MT-MMP) genes, Mmp15 and Mmp16, to mouse chromosomes 8 and 4, respectively. | Seldin MF et al |
| 19300513 | 2009 | Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. | Shiryaev SA et al |
| 9092507 | 1997 | Expression of three membrane-type matrix metalloproteinases (MT-MMPs) in rat vascular smooth muscle cells and characterization of MT3-MMPs with and without transmembrane domain. | Shofuda K et al |
| 15506641 | 2004 | Expression of mRNA for membrane-type 1, 2, and 3 matrix metalloproteinases in human laryngeal cancer. | Sun YN et al |
| 20858856 | 2010 | Membrane-type MMPs are indispensable for placental labyrinth formation and development. | Szabova L et al |
| 15895410 | 2005 | Expression pattern of four membrane-type matrix metalloproteinases in the normal and diseased mouse mammary gland. | Szabova L et al |
| 9037199 | 1997 | Isolation of a mouse MT2-MMP gene from a lung cDNA library and identification of its product. | Tanaka M et al |
| 21920357 | 2011 | Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development. | Tao G et al |
| 9736043 | 1998 | Differential expression and origin of membrane-type 1 and 2 matrix metalloproteinases (MT-MMPs) in association with MMP2 activation in injured human livers. | Théret N et al |
| 22018856 | 2012 | Boron induced expression of some stress-related genes in tomato. | Tombuloglu H et al |
| 9158005 | 1997 | Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. | Ueno H et al |
| 20369361 | 2010 | EMMPRIN (basigin/CD147) is involved in the morphogenesis of tooth germ in mouse molars. | Xie M et al |
| 10830778 | 2000 | Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in rheumatoid synovium. | Yamanaka H et al |
| 9179500 | 1997 | Assignment of human membrane-type matrix metalloproteinase-2 (MT2-MMP) gene to 16q12 by FISH and PCR-based human/rodent cell hybrid mapping panel analysis. | Yasumitsu H et al |
| 15581686 | 2005 | Microarray analysis of gene expression in chondrosarcoma cells treated with bee venom. | Yin CS et al |
| 16033774 | 2005 | The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. | Zhang J et al |
| 21751260 | 2011 | Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells. | Zhu S et al |
| 9461298 | 1997 | Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. | d'Ortho MP et al |
Other Information
Locus ID:
NCBI: 4324
MIM: 602261
HGNC: 7161
Ensembl: ENSG00000102996
Variants:
dbSNP: 4324
ClinVar: 4324
TCGA: ENSG00000102996
COSMIC: MMP15
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000102996 | ENST00000219271 | P51511 |
| ENSG00000102996 | ENST00000219271 | A0A024R6U8 |
| ENSG00000102996 | ENST00000570065 | H3BT97 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 34988996 | 2022 | Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive. | 3 |
| 35041985 | 2022 | MT2-MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. | 3 |
| 35062057 | 2022 | Changes in the expression of membrane type-matrix metalloproteinases genes (MMP14, MMP15, MMP16, MMP24) during treatment and their potential impact on the survival of patients with non-small cell lung cancer (NSCLC). | 5 |
| 34988996 | 2022 | Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive. | 3 |
| 35041985 | 2022 | MT2-MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. | 3 |
| 35062057 | 2022 | Changes in the expression of membrane type-matrix metalloproteinases genes (MMP14, MMP15, MMP16, MMP24) during treatment and their potential impact on the survival of patients with non-small cell lung cancer (NSCLC). | 5 |
| 32049862 | 2020 | Dominative role of MMP-14 over MMP-15 in human urinary bladder carcinoma on the basis of its enhanced specific activity. | 7 |
| 32517571 | 2020 | Effect of indole-3-carbinol on transcriptional profiling of wound-healing genes in macrophages of systemic lupus erythematosus patients: an RNA sequencing assay. | 4 |
| 32049862 | 2020 | Dominative role of MMP-14 over MMP-15 in human urinary bladder carcinoma on the basis of its enhanced specific activity. | 7 |
| 32517571 | 2020 | Effect of indole-3-carbinol on transcriptional profiling of wound-healing genes in macrophages of systemic lupus erythematosus patients: an RNA sequencing assay. | 4 |
| 30599080 | 2019 | LncRNA MAFG-AS1 facilitates the migration and invasion of NSCLC cell via sponging miR-339-5p from MMP15. | 33 |
| 30809850 | 2019 | The prognostic value of matrix metalloproteinase-7 and matrix metalloproteinase-15 in acute myeloid leukemia. | 9 |
| 30599080 | 2019 | LncRNA MAFG-AS1 facilitates the migration and invasion of NSCLC cell via sponging miR-339-5p from MMP15. | 33 |
| 30809850 | 2019 | The prognostic value of matrix metalloproteinase-7 and matrix metalloproteinase-15 in acute myeloid leukemia. | 9 |
| 29061881 | 2017 | E-cadherin cleavage by MT2-MMP regulates apical junctional signaling and epithelial homeostasis in the intestine. | 11 |
Citation
Emiko Ito ; Ikuo Yana ; Nariaki Matsuura
MMP15 (matrix metallopeptidase 15 (membrane-inserted))
Atlas Genet Cytogenet Oncol Haematol. 2012-10-01
Online version: http://atlasgeneticsoncology.org/gene/41392/mmp15-(matrix-metallopeptidase-15-(membrane-inserted))
