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MMP2 (matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase).

Identity

Other namesCLG4 (Collagenase Type IV),
CLG4A (Collagenase Type IV-A),
TBE-1(as secreted by H-ras oncogene-transformed human bronchial epithelial cells),
MMP-II.
HGNC (Hugo) MMP2
LocusID (NCBI) 4313
Location 16q12.2
Location_base_pair Starts at 55515474 and ends at 55540586 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
Description This gene can be found on chromosome 16 at location: 54,070,604-54,097,652
Transcription The DNA sequence contains 13 exons and the transcript length: 3,069 bps translated to a 660 residues protein.

Protein

 
  Domain structure of the MMP2.
  • Pre: signal sequence;
  • Pro: propeptide with a free zinc-ligating thiol (SH) group;
  • Zn: zinc-binding site;
  • II: collagen-binding fibronectin type II inserts;
  • H: hinge region;
    The hemopexin/vitronectin-like domain contains four repeats with the first and last linked by a disulfide bond.
  • Description MMP2 is a Zn+2 dependent endopeptidase, synthesized and secreted in zymogen form. The nascent form of the protein shows an N-terminal signal sequence ("pre" domain) that directs the protein to the endoplasmic reticulum. The pre domain is followed by a propeptide-"pro" domain that maintains enzyme-latency until cleaved or disrupted, and a catalytic domain that contains the conserved zinc-binding region. A hemopexin/vitronectin-like domain is also seen, that is connected to the catalytic domain by a hinge or linker region. The hemopexin domain is involved in TIMP (Tissue Inhibitors of Metallo-Proteinases) binding, the binding of certain substrates, membrane activation, and some proteolytic activities. It also shows a series of three head-to-tail cysteine-rich repeats within its catalytic domain. These inserts resemble the collagen-binding type II repeats of fibronectin and are required to bind and cleave collagen and elastin.

    The regulation of MMP-2 activity occurs at many levels, of which regulation through TIMP-2 and its cell surface receptor, MT1-MMP (MMP14) is critically decisive. At higher levels of TIMP-2, MT1-MMP forms a ternary complex with MMP-2 through, leaving no free MT1-MMP receptors, thereby inhibiting the activation of pro-MMP-2 by MT1-MMP. But at lower levels of TIMP-2, due to availability of free MT1-MMP, MT1-MMP mediated activation of MMP-2 is observed. Further data also indicates that expression of TIMP-2, MMP-2 and MT1-MMP (MMP-14) is co-regulated transcriptionally, demonstrating an intricate network of regulation. Pro-MMP-2 activation is also seen by complex signaling induced by ECM proteins like osteopontin, various cytokines for example IL-8 in endothelial cells and other factors.

    Expression MMP2 is tightly regulated at the transcriptional and post-transcriptional levels.
    Localisation Peri/extracellular
    Function Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests gelatin (denatured collagen), and types IV, V, VII, IX and X collagen. Physiologically, MMP-2 in coordination with other MMPs, play a role in normal tissue remodeling events such as embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP2 is also involved in osteoblastic bone formation and/or inhibits osteoclastic bone resorption.
    Homology Homology in amino acid sequence is seen with the other members of Metalloproteinase family especially with MMP-9.

    Mutations

    Germinal A G-to-A transition in codon 101 of exon 2 of MMP2 gene was detected in a Saudi family with idiopathic multicentric osteolysis. This mutation showed a replacement of an arginine by histidine (R101H) in the prodomain, a region highly conserved across species and other members of the MMP gene family that is involved in autoproteolytic activation of MMP2.
    In a case of Winchester Syndrome, a homozygous 1210G-A transition in exon 8 of the MMP2 gene, leads to glu-to-lys (E404K) substitution in the catalytic domain of the protein. The glutamic acid at codon 404 is believed to be essential for the peptidase activity of all metalloproteinases, as its carboxyl group catalyzes 2 proton transfers, helps stabilize the transition state, and triggers the release of the products.

    Implicated in

    Entity Elevated expression of MMP-2, along with MMP-9 is usually seen in invasive and highly tumorigenic cancers such as colorectal tumors, gastric carcinoma, pancreatic carcinoma, breast cancer, oral cancer, melanoma, malignant gliomas, Chondrosarcoma, gastrointestinal adenocarcinoma. Levels are also increased in malignant astrocytomas, carcinomatous meningitis, and brain metastases.
    Oncogenesis MMPs promote tumor progression and metastasis in invasive cancers by degradation of the ECM (ExtraCellular Matrix), which consists of two main components: Basement membranes and interstitial connective tissue. Though ECM comprises of many proteins (laminin-5, proteoglycans, entactin, osteonectin) collagen IV is the major element. MMP-2 & MMP-9 efficiently degrade collagen IV and laminin-5 thereby, assisting the metastatic cancerous cells to pass through the basement membrane. The degradation of ECM not only assists migration of metastatic cancerous cells, but also allows enhanced tumor growth by providing necessary space. Further, it is noteworthy that the ratio of active to latent form of MMP-2 increased with tumor progression in invasive cancers. MMP-2, with its family members also promotes angiogenesis (a critical process required for tumor cell survival) by degrading the vascular basement membrane and the interstitium.
      
    Note Arthritis, Autosomal recessive osteolysis disorder, Coronary Artery disease, pulmonary-emphysema and diabetic retinopathy.
      

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

    External links

    Nomenclature
    HGNC (Hugo)MMP2   7166
    Cards
    AtlasMMP2ID41396ch16q13
    Entrez_Gene (NCBI)MMP2  4313  matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)
    GeneCards (Weizmann)MMP2
    Ensembl (Hinxton)ENSG00000087245 [Gene_View]  chr16:55515474-55540586 [Contig_View]  MMP2 [Vega]
    ICGC DataPortalENSG00000087245
    AceView (NCBI)MMP2
    Genatlas (Paris)MMP2
    WikiGenes4313
    SOURCE (Princeton)NM_001127891 NM_004530
    Genomic and cartography
    GoldenPath (UCSC)MMP2  -  16q12.2   chr16:55515474-55540586 +  16q13-q21   [Description]    (hg19-Feb_2009)
    EnsemblMMP2 - 16q13-q21 [CytoView]
    Mapping of homologs : NCBIMMP2 [Mapview]
    OMIM120360   259600   
    Gene and transcription
    Genbank (Entrez)AK301536 AK310314 AK312711 AL046162 AL542407
    RefSeq transcript (Entrez)NM_001127891 NM_004530
    RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NG_008989 NT_010498 NW_001838289 NW_004929402
    Consensus coding sequences : CCDS (NCBI)MMP2
    Cluster EST : UnigeneHs.513617 [ NCBI ]
    CGAP (NCI)Hs.513617
    Alternative Splicing : Fast-db (Paris)GSHG0011197
    Alternative Splicing GalleryENSG00000087245
    Gene ExpressionMMP2 [ NCBI-GEO ]     MMP2 [ SEEK ]   MMP2 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP08253 (Uniprot)
    NextProtP08253  [Medical]
    With graphics : InterProP08253
    Splice isoforms : SwissVarP08253 (Swissvar)
    Catalytic activity : Enzyme3.4.24.24 [ Enzyme-Expasy ]   3.4.24.243.4.24.24 [ IntEnz-EBI ]   3.4.24.24 [ BRENDA ]   3.4.24.24 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)CYSTEINE_SWITCH (PS00546)    FN2_1 (PS00023)    FN2_2 (PS51092)    HEMOPEXIN (PS00024)    HEMOPEXIN_2 (PS51642)    ZINC_PROTEASE (PS00142)   
    Domains : Interpro (EBI)72kDa_collagenase    FN_type2_col-bd    Hemopexin-like_dom    Hemopexin-like_repeat    Hemopexin_CS    Kringle-like    MetalloPept_cat_dom    Pept_M10_metallopeptidase    Pept_M10A    Pept_M10A_Zn_BS    Peptidase_Metallo    Peptidoglycan-bd-like   
    Related proteins : CluSTrP08253
    Domain families : Pfam (Sanger)fn2 (PF00040)    Hemopexin (PF00045)    Peptidase_M10 (PF00413)    PG_binding_1 (PF01471)   
    Domain families : Pfam (NCBI)pfam00040    pfam00045    pfam00413    pfam01471   
    Domain families : Smart (EMBL)FN2 (SM00059)  HX (SM00120)  ZnMc (SM00235)  
    DMDM Disease mutations4313
    Blocks (Seattle)P08253
    PDB (SRS)1CK7    1CXW    1EAK    1GEN    1GXD    1HOV    1J7M    1KS0    1QIB    1RTG    3AYU   
    PDB (PDBSum)1CK7    1CXW    1EAK    1GEN    1GXD    1HOV    1J7M    1KS0    1QIB    1RTG    3AYU   
    PDB (IMB)1CK7    1CXW    1EAK    1GEN    1GXD    1HOV    1J7M    1KS0    1QIB    1RTG    3AYU   
    PDB (RSDB)1CK7    1CXW    1EAK    1GEN    1GXD    1HOV    1J7M    1KS0    1QIB    1RTG    3AYU   
    Human Protein AtlasENSG00000087245
    Peptide AtlasP08253
    HPRD00386
    IPIIPI00027780   IPI01009185   IPI00895858   
    Protein Interaction databases
    DIP (DOE-UCLA)P08253
    IntAct (EBI)P08253
    FunCoupENSG00000087245
    BioGRIDMMP2
    InParanoidP08253
    Interologous Interaction database P08253
    IntegromeDBMMP2
    STRING (EMBL)MMP2
    Ontologies - Pathways
    Ontology : AmiGOangiogenesis  response to hypoxia  blood vessel maturation  intramembranous ossification  metalloendopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  proteinaceous extracellular matrix  extracellular space  nucleus  mitochondrion  plasma membrane  proteolysis  embryo implantation  zinc ion binding  extracellular matrix disassembly  sarcomere  extracellular matrix organization  collagen catabolic process  cellular protein metabolic process  face morphogenesis  bone trabecula formation  cellular response to amino acid stimulus  
    Ontology : EGO-EBIangiogenesis  response to hypoxia  blood vessel maturation  intramembranous ossification  metalloendopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  proteinaceous extracellular matrix  extracellular space  nucleus  mitochondrion  plasma membrane  proteolysis  embryo implantation  zinc ion binding  extracellular matrix disassembly  sarcomere  extracellular matrix organization  collagen catabolic process  cellular protein metabolic process  face morphogenesis  bone trabecula formation  cellular response to amino acid stimulus  
    Pathways : BIOCARTAInhibition of Matrix Metalloproteinases [Genes]   
    Pathways : KEGGLeukocyte transendothelial migration    GnRH signaling pathway    Estrogen signaling pathway    Pathways in cancer    Proteoglycans in cancer    Bladder cancer   
    REACTOMEP08253 [protein]
    REACTOME PathwaysREACT_196873 Extracellular matrix organization [pathway]
    REACTOME PathwaysREACT_118779 Extracellular matrix organization [pathway]
    REACTOME PathwaysREACT_17015 Metabolism of proteins [pathway]
    Protein Interaction DatabaseMMP2
    Wikipedia pathwaysMMP2
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)MMP2
    SNP (GeneSNP Utah)MMP2
    SNP : HGBaseMMP2
    Genetic variants : HAPMAPMMP2
    1000_GenomesMMP2 
    ICGC programENSG00000087245 
    CONAN: Copy Number AnalysisMMP2 
    Somatic Mutations in Cancer : COSMICMMP2 
    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
    LOVD (Leiden Open Variation Database)Mendelian genes
    Mutations and Diseases : HGMDMMP2
    OMIM120360    259600   
    MedgenMMP2
    GENETestsMMP2
    Disease Genetic AssociationMMP2
    Huge Navigator MMP2 [HugePedia]  MMP2 [HugeCancerGEM]
    Genomic VariantsMMP2  MMP2 [DGVbeta]
    Exome VariantMMP2
    dbVarMMP2
    ClinVarMMP2
    snp3D : Map Gene to Disease4313
    General knowledge
    Homologs : HomoloGeneMMP2
    Homology/Alignments : Family Browser (UCSC)MMP2
    Phylogenetic Trees/Animal Genes : TreeFamMMP2
    Chemical/Protein Interactions : CTD4313
    Chemical/Pharm GKB GenePA30877
    Clinical trialMMP2
    Cancer Resource (Charite)ENSG00000087245
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineMMP2
    iHOPMMP2

    Bibliography

    An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides.
    Hangauer DG, Monzingo AF, Matthews BW
    Biochemistry. 1984 ; 23 (24) : 5730-5741.
    PMID 6525336
     
    Activity of type IV collagenases in benign and malignant breast disease.
    Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR
    British journal of cancer. 1993 ; 67 (5) : 1126-1131.
    PMID 8494711
     
    Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed.
    Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, Tryggvason K
    Science (New York, N.Y.). 1999 ; 284 (5420) : 1667-1670.
    PMID 10356396
     
    Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.
    Stetler-Stevenson WG
    The Journal of clinical investigation. 1999 ; 103 (9) : 1237-1241.
    PMID 10225966
     
    Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis.
    Zeng ZS, Cohen AM, Guillem JG
    Carcinogenesis. 1999 ; 20 (5) : 749-755.
    PMID 10334190
     
    Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis.
    Goldbach-Mansky R, Lee JM, Hoxworth JM, Smith D 2nd, Duray P, Schumacher RH Jr, Yarboro CH, Klippel J, Kleiner D, El-Gabalawy HS
    Arthritis research. 2000 ; 2 (2) : 145-153.
    PMID 11062605
     
    Matrix Metalloproteinases and TIMPs.
    Woessner JF, Nagase H
    New York. : page Ox.
     
    The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.
    John A, Tuszynski G
    Pathology oncology research : POR. 2001 ; 7 (1) : 14-23.
    PMID 11349215
     
    Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.
    Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ
    Nature genetics. 2001 ; 28 (3) : 261-265.
    PMID 11431697
     
    Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells.
    Philip S, Bulbule A, Kundu GC
    The Journal of biological chemistry. 2001 ; 276 (48) : 44926-44935.
    PMID 11564733
     
    Don't mess with the matrix.
    Vu TH
    Nature genetics. 2001 ; 28 (3) : 202-203.
    PMID 11431682
     
    Matrix metalloproteinases in arthritic disease.
    Murphy G, Knˆ§uper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I
    Arthritis research. 2002 ; 4 Suppl 3 : S39-S49.
    PMID 12110122
     
    Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials.
    Bloomston M, Zervos EE, Rosemurgy AS 2nd
    Annals of surgical oncology. 2002 ; 9 (7) : 668-674.
    PMID 12167581
     
    Matrix metalloproteinases as novel disease markers in Takayasu arteritis.
    Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, Nakamura T, Yamashita S, Matsuzawa Y
    Circulation. 2003 ; 108 (12) : 1469-1473.
    PMID 12952836
     
    Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy.
    Noda K, Ishida S, Inoue M, Obata K, Oguchi Y, Okada Y, Ikeda E
    Investigative ophthalmology & visual science. 2003 ; 44 (5) : 2163-2170.
    PMID 12714657
     
    Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha /IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways.
    Philip S, Kundu GC
    The Journal of biological chemistry. 2003 ; 278 (16) : 14487-14497.
    PMID 12473670
     
    Matrix metalloproteinase-2: mechanism and regulation of NF-kappaB-mediated activation and its role in cell motility and ECM-invasion.
    Philip S, Bulbule A, Kundu GC
    Glycoconjugate journal. 2004 ; 21 (8-9) : 429-441.
    PMID 15750784
     
    Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis.
    Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK
    Angiogenesis. 2005 ; 8 (1) : 63-71.
    PMID 16132619
     
    Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.
    Zankl A, Bonafˆ© L, Calcaterra V, Di Rocco M, Superti-Furga A
    Clinical genetics. 2005 ; 67 (3) : 261-266.
    PMID 15691365
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written10-2005Gopal Chandra Kundu, Pralhad Deepak Patil
    CSIR-JRF,c/o Dr. G. C. Kundu, National Center for Cell Science, NCCS Complex, Ganeshkhind, Pune(Maharastra)-411007, India

    Citation

    This paper should be referenced as such :
    Kundu, GC ; Patil, DP
    MMP2 (matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase).
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):88-90.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/MMP2ID41396ch16q13.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon Oct 13 13:29:39 CEST 2014

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