MMP15 (matrix metallopeptidase 15 (membrane-inserted))

2012-10-01 Emiko Ito , Ikuo Yana , Nariaki Matsuura Affiliation

Department of Molecular Pathology, Graduate School of Medicine, Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan

Identity

HGNC

MMP15

LOCATION

16q21

LOCUSID

4324

ALIAS

MMP-15,MT2-MMP,MT2MMP,MTMMP2,SMCP-2

FUSION GENES

Show Gene Fusions

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.

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).

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).

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).

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)

100

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Extracellular matrix organization	REACTOME	R-HSA-1474244
Degradation of the extracellular matrix	REACTOME	R-HSA-1474228
Activation of Matrix Metalloproteinases	REACTOME	R-HSA-1592389
Collagen degradation	REACTOME	R-HSA-1442490

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
16983145	2006	A cancer cell metalloprotease triad regulates the basement membrane transmigration program.	148
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
20673868	2010	A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).	36
20452482	2010	Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes.	26
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.	23
21036765	2010	Immunochemical staining of MT2-MMP correlates positively to angiogenesis of human esophageal cancer.	21
23228395	2013	Multiple steps of HLA-G in ovarian carcinoma metastasis: alter NK cytotoxicity and induce matrix metalloproteinase-15 (MMP-15) expression.	16
20117087	2010	The role of MT2-MMP in cancer progression.	11
20628086	2010	Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.	11
21751260	2011	Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells.	10

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))