MMP19 (matrix metallopeptidase 19)

2013-10-01   King Chi Chan , Maria Li Lung 

Department of Clinical Oncology, Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, P.R. China

Identity

HGNC
LOCATION
12q13.2
LOCUSID
ALIAS
CODA,MMP18,RASI-1

DNA/RNA

Atlas Image
Alternative splicing results in multiple transcript variants for this gene (provided by RefSeq, Jan 2013). With reference to UniProtKB database, variant 1 represents the longest transcript and encodes isoform 1 (508 aa, 57 kDa, also known as RASI-1). Variant 2 encoded protein isoform 2 (222 aa, 25 kDa, also known as RASI-9). Variant 3 encoded protein isoform 3 (63 aa, 6 kDa, also known as RASI-6). Isoform 1 has been described as the canonical sequence and all the information described here, unless stated, refers to isoform 1.

Description

MMP-19 can be found at chromosome 12q13.2 at location 56229214-56236767. The DNA sequence contains nine exons and eight introns, spanning 7,55 kb.

Transcription

The MMP-19 promoter contains a TATA-box at position -29 and AP-1 binding site at position -73. Potential binding sites for other transcription factors such as NFκB, AP-2, and SP-1 also exist (Mueller et al., 2000).

Proteins

Atlas Image
MMP-19 shares a typical MMP structural domain, containing the signal peptide, propeptide, catalytic domain, hinge region, and four hemopexin repeats (Pendás et al., 1997).

Description

MMP-19 is a secreted protein. It contains a signal peptide for targeting to secretory vesicles. Like most secreted MMPs, MMP-19 is translated and secreted as catalytic inactive proproteins (zymogens), which needed to be activated by proteolytic cleavage of the propeptide region by other extracellular matrix (EMC) proteinases (Ra and Parks, 2007).
MMP-19 is a zinc-dependent endopeptidase. The catalytic domain contains the active site for zinc ion binding and functions in catalytic activity such as substrate degradation. The hemopexin domain is responsible for substrate recognition (Ra and Parks, 2007).
The catalytic activities of MMPs were reported to be regulated by tissue inhibitor of metalloproteinases (TIMPs). MMP-19 is reported to be strongly inhibited by TIMP-2, TIMP-3, and TIMP-4, and less efficiently by TIMP-1 (Clark et al., 2008).

Expression

MMP-19 was found to be expressed in a wide range of normal tissue types, such as nasopharyngeal epithelial cells, lung, breast, skin, intestine, pancreas, spleen, and ovary. MMP-19 was down-regulated or lost during neoplastic progression in nasopharyngeal carcinoma (NPC), mammary gland tumor, skin neoplasm, intestine, and colon cancers (Pendás et al., 1997; Djonov et al., 2001; Impola et al., 2003; Bister et al., 2004; Chan et al., 2011).

Localisation

MMP-19 is located in the cytoplasm and secreted into the extracellular matrix.

Function

MMP-19 is a member of the MMP family of zinc-dependent endopeptidases. The catalytic domain responsible for degradation of various components of the ECM include collagen type IV, nidogen-1, fibronectin, tenascin-C isoform, aggrecan, and laminin-5-gamma-2-chain (Stracke et al., 2000; Shiomi et al., 2010). MMP-19 is involved in many physiological activities such as cell proliferation, migration, and anti-angiogenesis.

Implicated in

Entity name
Various cancers
Note
Due to the ability of MMPs to degrade a variety of substrates, which may be involved in both cancer progression and repression, the role of MMP-19 in cancer development is as controversial as for all other MMPs.
MMP-19 is reported to cleave insulin-like growth factor binding protein-3 (IGFBP-3), thereby causing the release of IGF-1 and enhanced human keratinocyte cell proliferation, migration, and adhesion on type I collagen (Sadowski et al., 2003). Also, MMP-19 was reported to process the laminin-5-gamma-2-chain in keratinocyte cells, which leads to the integrin switch favoring epithelial cell migration (Sadowski et al., 2005).
On the other hand, a MMP-19 deficiency mouse model increased the onset of skin tumor invasion and vascularization, implicating the role of MMP-19 in inhibition of tumor invasion and anti-angiogenesis (Jost et al., 2006).
The anti-angiogenic role of MMP-19 was demonstrated in the tube formation assay in human microvascular endothelial cells (HMEC-1). MMP-19 inhibited tube formation by degradation of nidogen-1, which is a scaffolding protein required for stabilizing new capillary formation (Titz et al., 2004). Further studies of MMP-19 on endothelial cells suggested other mechanisms of MMP-19 in inhibition of angiogenesis. MMP-19 digests plasminogen to generate angiostatin-like fragments, which are antagonists of angiogenesis and inhibit migration and proliferation of endothelial cells (Brauer et al., 2011).
Functional studies of MMP-19 demonstrated its tumor suppressive and anti-angiogenesis functions in nasopharyngeal carcinoma (NPC). MMP-19 reduces colony-forming ability of NPC cells and suppresses tumor formation in nude mice. Also, MMP-19 reduces tube-forming ability in human umbilical vein endothelial cells (HuVEC) and human microvascular endothelial cells (HMEC-1). The anti-angiogenic activity of MMP-19 in NPC is associated with reduction of secreted vascular endothelial growth factor (VEGF) in the conditioned media (Chan et al., 2011). Recent study in NPC cells demonstrated MMP-19 increased cisplatin sensitivity through production of γ-H2AX and attenuation of NER activity to repair cisplatin-induced DNA damage, therefore increasing the cisplatin-induced apoptosis in NPC (Liu et al., 2013).
Entity name
Rheumatoid arthritis (RA)
Note
MMP-19 was first isolated as an autoantigen from the synovium of a rheumatoid arthritis patient suggesting its role in RA-associated joint tissue destruction (Sedlacek et al., 1998).

Bibliography

Pubmed IDLast YearTitleAuthors
151858742004Differential expression of three matrix metalloproteinases, MMP-19, MMP-26, and MMP-28, in normal and inflamed intestine and colon cancer.Bister VO et al
217873932011Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen.Brauer R et al
211659532011Catalytic activity of Matrix metalloproteinase-19 is essential for tumor suppressor and anti-angiogenic activities in nasopharyngeal carcinoma.Chan KC et al
182584752008The regulation of matrix metalloproteinases and their inhibitors.Clark IM et al
115920922001MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours.Djonov V et al
125160882003Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation.Impola U et al
167074482006Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice.Jost M et al
239560562013Overexpression of asparagine synthetase and matrix metalloproteinase 19 confers cisplatin sensitivity in nasopharyngeal carcinoma cells.Liu RY et al
109034352000Structure of the human MMP-19 gene.Mueller MS et al
90201451997Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution.Pendás AM et al
176696412007Control of matrix metalloproteinase catalytic activity.Ra HJ et al
158684102005Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.Sadowski T et al
95628661998Matrix metalloproteinase MMP-19 (RASI-1) is expressed on the surface of activated peripheral blood mononuclear cells and is detected as an autoantigen in rheumatoid arthritis.Sedlacek R et al
205942692010Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases.Shiomi T et al
109224682000Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP).Stracke JO et al
152415582004Activity of MMP-19 inhibits capillary-like formation due to processing of nidogen-1.Titz B et al

Other Information

Locus ID:

NCBI: 4327
MIM: 601807
HGNC: 7165
Ensembl: ENSG00000123342

Variants:

dbSNP: 4327
ClinVar: 4327
TCGA: ENSG00000123342
COSMIC: MMP19

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000123342ENST00000322569Q99542
ENSG00000123342ENST00000409200Q99542
ENSG00000123342ENST00000548629F8W1C3
ENSG00000123342ENST00000548882A6ND33
ENSG00000123342ENST00000552763B4DNP3
ENSG00000123342ENST00000552872Q99542

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Collagen degradationREACTOMER-HSA-1442490

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
206738682010A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).36
129372692003Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3.28
228595222012Matrix metalloproteinase-19 is a key regulator of lung fibrosis in mice and humans.28
204524822010Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes.26
179804492008Expression of matrix metalloproteinases MMP-1, MMP-11 and MMP-19 is correlated with the WHO-grading of human malignant gliomas.22
158684102005Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.21
262922592015Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression.19
258409982015Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients.16
252508552014Matrix metalloproteinase-19 promotes metastatic behavior in vitro and is associated with increased mortality in non-small cell lung cancer.15

Citation

King Chi Chan ; Maria Li Lung

MMP19 (matrix metallopeptidase 19)

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: http://atlasgeneticsoncology.org/gene/41395/mmp19