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

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/css/lib/bootstrap.min.css