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MMP19 (matrix metallopeptidase 19)

Written2013-10King Chi Chan, Maria Li Lung
Department of Clinical Oncology, Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, P.R. China

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMMP18
matrix metalloproteinase 19
Alias_symbol (synonym)RASI-1
Other alias
HGNC (Hugo) MMP19
LocusID (NCBI) 4327
Atlas_Id 41395
Location 12q13.2  [Link to chromosome band 12q13]
Location_base_pair Starts at 55835430 and ends at 55842983 bp from pter ( according to hg19-Feb_2009)  [Mapping MMP19.png]

DNA/RNA

 
  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).

Protein

 
  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

Note
  
Entity 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 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

Differential expression of three matrix metalloproteinases, MMP-19, MMP-26, and MMP-28, in normal and inflamed intestine and colon cancer.
Bister VO, Salmela MT, Karjalainen-Lindsberg ML, Uria J, Lohi J, Puolakkainen P, Lopez-Otin C, Saarialho-Kere U.
Dig Dis Sci. 2004 Apr;49(4):653-61.
PMID 15185874
 
Matrix metalloproteinase-19 inhibits growth of endothelial cells by generating angiostatin-like fragments from plasminogen.
Brauer R, Beck IM, Roderfeld M, Roeb E, Sedlacek R.
BMC Biochem. 2011 Jul 25;12:38. doi: 10.1186/1471-2091-12-38.
PMID 21787393
 
Catalytic activity of Matrix metalloproteinase-19 is essential for tumor suppressor and anti-angiogenic activities in nasopharyngeal carcinoma.
Chan KC, Ko JM, Lung HL, Sedlacek R, Zhang ZF, Luo DZ, Feng ZB, Chen S, Chen H, Chan KW, Tsao SW, Chua DT, Zabarovsky ER, Stanbridge EJ, Lung ML.
Int J Cancer. 2011 Oct 15;129(8):1826-37. doi: 10.1002/ijc.25855. Epub 2011 Apr 1.
PMID 21165953
 
The regulation of matrix metalloproteinases and their inhibitors.
Clark IM, Swingler TE, Sampieri CL, Edwards DR.
Int J Biochem Cell Biol. 2008;40(6-7):1362-78. doi: 10.1016/j.biocel.2007.12.006. Epub 2007 Dec 24. (REVIEW)
PMID 18258475
 
MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours.
Djonov V, Hogger K, Sedlacek R, Laissue J, Draeger A.
J Pathol. 2001 Sep;195(2):147-55.
PMID 11592092
 
Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation.
Impola U, Toriseva M, Suomela S, Jeskanen L, Hieta N, Jahkola T, Grenman R, Kahari VM, Saarialho-Kere U.
Int J Cancer. 2003 Mar 1;103(6):709-16.
PMID 12516088
 
Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice.
Jost M, Folgueras AR, Frerart F, Pendas AM, Blacher S, Houard X, Berndt S, Munaut C, Cataldo D, Alvarez J, Melen-Lamalle L, Foidart JM, Lopez-Otin C, Noel A.
Cancer Res. 2006 May 15;66(10):5234-41.
PMID 16707448
 
Overexpression of asparagine synthetase and matrix metalloproteinase 19 confers cisplatin sensitivity in nasopharyngeal carcinoma cells.
Liu RY, Dong Z, Liu J, Zhou L, Huang W, Khoo SK, Zhang Z, Petillo D, Teh BT, Qian CN, Zhang JT.
Mol Cancer Ther. 2013 Oct;12(10):2157-66. doi: 10.1158/1535-7163.MCT-12-1190. Epub 2013 Aug 16.
PMID 23956056
 
Structure of the human MMP-19 gene.
Mueller MS, Mauch S, Sedlacek R.
Gene. 2000 Jul 11;252(1-2):27-37.
PMID 10903435
 
Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution.
Pendas AM, Knauper V, Puente XS, Llano E, Mattei MG, Apte S, Murphy G, Lopez-Otin C.
J Biol Chem. 1997 Feb 14;272(7):4281-6.
PMID 9020145
 
Control of matrix metalloproteinase catalytic activity.
Ra HJ, Parks WC.
Matrix Biol. 2007 Oct;26(8):587-96. Epub 2007 Jul 7. (REVIEW)
PMID 17669641
 
Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration.
Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch E, Titz B, Sedlacek R.
Cell Mol Life Sci. 2005 Apr;62(7-8):870-80.
PMID 15868410
 
Matrix 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, Mauch S, Kolb B, Schatzlein C, Eibel H, Peter HH, Schmitt J, Krawinkel U.
Immunobiology. 1998 Feb;198(4):408-23.
PMID 9562866
 
Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases.
Shiomi T, Lemaitre V, D'Armiento J, Okada Y.
Pathol Int. 2010 Jul;60(7):477-96. doi: 10.1111/j.1440-1827.2010.02547.x. (REVIEW)
PMID 20594269
 
Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP).
Stracke JO, Fosang AJ, Last K, Mercuri FA, Pendas AM, Llano E, Perris R, Di Cesare PE, Murphy G, Knauper V.
FEBS Lett. 2000 Jul 28;478(1-2):52-6.
PMID 10922468
 
Activity of MMP-19 inhibits capillary-like formation due to processing of nidogen-1.
Titz B, Dietrich S, Sadowski T, Beck C, Petersen A, Sedlacek R.
Cell Mol Life Sci. 2004 Jul;61(14):1826-33.
PMID 15241558
 

Citation

This paper should be referenced as such :
Chan, KC ; Lung, ML
MMP19 (matrix metallopeptidase 19)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):327-329.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MMP19ID41395ch12q13.html


External links

Nomenclature
HGNC (Hugo)MMP19   7165
Cards
AtlasMMP19ID41395ch12q13
Entrez_Gene (NCBI)MMP19  4327  matrix metallopeptidase 19
AliasesCODA; MMP18; RASI-1
GeneCards (Weizmann)MMP19
Ensembl hg19 (Hinxton)ENSG00000123342 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000123342 [Gene_View]  chr12:55835430-55842983 [Contig_View]  MMP19 [Vega]
ICGC DataPortalENSG00000123342
TCGA cBioPortalMMP19
AceView (NCBI)MMP19
Genatlas (Paris)MMP19
WikiGenes4327
SOURCE (Princeton)MMP19
Genetics Home Reference (NIH)MMP19
Genomic and cartography
GoldenPath hg38 (UCSC)MMP19  -     chr12:55835430-55842983 -  12q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MMP19  -     12q13.2   [Description]    (hg19-Feb_2009)
EnsemblMMP19 - 12q13.2 [CytoView hg19]  MMP19 - 12q13.2 [CytoView hg38]
Mapping of homologs : NCBIMMP19 [Mapview hg19]  MMP19 [Mapview hg38]
OMIM601807   611543   
Gene and transcription
Genbank (Entrez)AK225939 AK297999 AK303202 AL545199 BC030206
RefSeq transcript (Entrez)NM_001032360 NM_001272101 NM_002429 NM_022790 NM_022792
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MMP19
Cluster EST : UnigeneHs.591033 [ NCBI ]
CGAP (NCI)Hs.591033
Alternative Splicing GalleryENSG00000123342
Gene ExpressionMMP19 [ NCBI-GEO ]   MMP19 [ EBI - ARRAY_EXPRESS ]   MMP19 [ SEEK ]   MMP19 [ MEM ]
Gene Expression Viewer (FireBrowse)MMP19 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4327
GTEX Portal (Tissue expression)MMP19
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99542   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ99542  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ99542
Splice isoforms : SwissVarQ99542
Catalytic activity : Enzyme3.4.24.- [ Enzyme-Expasy ]   3.4.24.-3.4.24.- [ IntEnz-EBI ]   3.4.24.- [ BRENDA ]   3.4.24.- [ KEGG ]   
PhosPhoSitePlusQ99542
Domaine pattern : Prosite (Expaxy)HEMOPEXIN_2 (PS51642)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)Hemopexin-like_dom    Hemopexin-like_repeat    M10A_MMP    MetalloPept_cat_dom    Pept_M10_metallopeptidase    Pept_M10A    Pept_M10A_stromelysin-type    Peptidase_Metallo    Peptidoglycan-bd-like   
Domain families : Pfam (Sanger)Hemopexin (PF00045)    Peptidase_M10 (PF00413)    PG_binding_1 (PF01471)   
Domain families : Pfam (NCBI)pfam00045    pfam00413    pfam01471   
Domain families : Smart (EMBL)HX (SM00120)  ZnMc (SM00235)  
Conserved Domain (NCBI)MMP19
DMDM Disease mutations4327
Blocks (Seattle)MMP19
SuperfamilyQ99542
Human Protein AtlasENSG00000123342
Peptide AtlasQ99542
HPRD03486
IPIIPI00016067   IPI00218151   IPI00218152   IPI00791255   IPI00910832   IPI00009733   IPI01021982   IPI01021828   IPI00651742   IPI00909902   
Protein Interaction databases
DIP (DOE-UCLA)Q99542
IntAct (EBI)Q99542
FunCoupENSG00000123342
BioGRIDMMP19
STRING (EMBL)MMP19
ZODIACMMP19
Ontologies - Pathways
QuickGOQ99542
Ontology : AmiGOangiogenesis  ovarian follicle development  ovulation from ovarian follicle  luteolysis  metalloendopeptidase activity  metalloendopeptidase activity  serine-type endopeptidase activity  calcium ion binding  extracellular region  proteinaceous extracellular matrix  extracellular space  proteolysis  zinc ion binding  response to hormone  extracellular matrix disassembly  cell differentiation  collagen catabolic process  response to cAMP  
Ontology : EGO-EBIangiogenesis  ovarian follicle development  ovulation from ovarian follicle  luteolysis  metalloendopeptidase activity  metalloendopeptidase activity  serine-type endopeptidase activity  calcium ion binding  extracellular region  proteinaceous extracellular matrix  extracellular space  proteolysis  zinc ion binding  response to hormone  extracellular matrix disassembly  cell differentiation  collagen catabolic process  response to cAMP  
REACTOMEQ99542 [protein]
REACTOME PathwaysR-HSA-1474228 [pathway]   
NDEx NetworkMMP19
Atlas of Cancer Signalling NetworkMMP19
Wikipedia pathwaysMMP19
Orthology - Evolution
OrthoDB4327
GeneTree (enSembl)ENSG00000123342
Phylogenetic Trees/Animal Genes : TreeFamMMP19
HOVERGENQ99542
HOGENOMQ99542
Homologs : HomoloGeneMMP19
Homology/Alignments : Family Browser (UCSC)MMP19
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMMP19 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MMP19
dbVarMMP19
ClinVarMMP19
1000_GenomesMMP19 
Exome Variant ServerMMP19
ExAC (Exome Aggregation Consortium)MMP19 (select the gene name)
Genetic variants : HAPMAP4327
Genomic Variants (DGV)MMP19 [DGVbeta]
DECIPHERMMP19 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMMP19 
Mutations
ICGC Data PortalMMP19 
TCGA Data PortalMMP19 
Broad Tumor PortalMMP19
OASIS PortalMMP19 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMMP19  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMMP19
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MMP19
DgiDB (Drug Gene Interaction Database)MMP19
DoCM (Curated mutations)MMP19 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MMP19 (select a term)
intoGenMMP19
NCG5 (London)MMP19
Cancer3DMMP19(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601807    611543   
Orphanet
MedgenMMP19
Genetic Testing Registry MMP19
NextProtQ99542 [Medical]
TSGene4327
GENETestsMMP19
Target ValidationMMP19
Huge Navigator MMP19 [HugePedia]
snp3D : Map Gene to Disease4327
BioCentury BCIQMMP19
ClinGenMMP19
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4327
Chemical/Pharm GKB GenePA30876
Clinical trialMMP19
Miscellaneous
canSAR (ICR)MMP19 (select the gene name)
Probes
Litterature
PubMed63 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMMP19
EVEXMMP19
GoPubMedMMP19
iHOPMMP19
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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