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MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase))

Identity

Other namesCLG4 (Collagenase Type IV),
CLG4B (Collagenase Type IV-B),
GELB (Gelatinase B)
HGNC MMP9
Location 20q11.2-q13.1

DNA/RNA

Description This gene can be found on Chromosome 26 at location: 44,070,954 - 44,078,606.
Transcription The DNA sequence contains 13 exons and the transcript length: 2,335 bps translated to a 707 residues protein.

Protein

 
  Domain structure of the MMP9.
  • 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 MMP-9 is a Zn+2 dependent endopeptidase, synthesized and secreted in monomeric form as zymogen. The structure is almost similar to MMP2, another member of matrixmetalloproteinase family. 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 e.g. TIMP-1 & TIMP-3, 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.
    Like other proteolytic enzymes, MMP-9 is first synthesized as inactive proenzyme or zymogens. Activation of proMMP-9 is mediated by plasminogen activator/plasmin (PA/plasmin) system. The regulation of MMP-9 activity is also controlled through TIMP-3.
    Expression MMP-9 expression is regulated by several cytokines and growth factors, including interleukins, interferons, EGF (Epidermal growth factor), NGF (Nerve growth factor), basic FGF (Fibroblast growth factor), VEGF (Vascular endothelial growth factor), PDGF (Platelet derived growth), TNF-a (Tumor necrosis factor), TGF-b (Tranforming growth factor), the extracellular matrix metalloproteinase inducer EMMPRIN and also osteopontin. Many of these stimuli induce the expression and/or activation of c-fos and c-jun proto-oncogene products, which heterodimerize and bind activator protein-1 (AP-1) sites within of MMP9 gene promoters.
    Localisation Peri/extracellular
    Function Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests decorin, elastin, fibrillin, laminin, gelatin (denatured collagen), and types IV, V, XI and XVI collagen and also activates growth factors like proTGFb and proTNFa. Physiologically, MMP-9 in coordination with other MMPs, play a role in normal tissue remodeling events such as neurite gowth, embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP-9 with other MMPs 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-2.

    Mutations

    Germinal Not yet reported.

    Implicated in

    Entity Invasive and highly tumorigenic cancers
    Disease Elevated expression of MMP-9, along with MMP-2 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-9 increased with tumor progression in invasive cancers. MMP-9, with its family members also promotes angiogenesis (a critical process required for tumor cell survival) by degrading the vascular basement membrane interstitium and also by releasing sequestered VEGF, which is a well know angiogenic molecule. Localization of MMP9 to the cell surface is required to promote tumor invasion and angiogenesis.
      
    Entity Arthritis, autosomal recessive osteolysis disorder, coronary artery disease, pulmonary-emphysema and diabetic retinopathy.
      

    External links

    Nomenclature
    HGNCMMP9   7176
    Entrez_GeneMMP9  4318  matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)
    Cards
    AtlasMMP9ID41408ch20q11
    GeneCardsMMP9
    EnsemblMMP9 [Search_View]   ENSG00000100985 [Gene_View]
    GenatlasMMP9
    GeneLynxMMP9
    eGenomeMMP9
    euGene4318
    Genomic and cartography
    GoldenPathMMP9  -     chr20:44070954-44078607 +  20q12-q13   [Description]    (hg18-Mar_2006)
    EnsemblMMP9 - 20q12-q13 [CytoView]
    NCBIMapview
    OMIMDisease map [OMIM]
    HomoloGeneMMP9
    Gene and transcription
    GenbankAK313137 [ ENTREZ ]
    GenbankAW468235 [ ENTREZ ]
    GenbankBC006093 [ ENTREZ ]
    GenbankCN288579 [ ENTREZ ]
    GenbankDQ896791 [ ENTREZ ]
    RefSeqNM_004994 [ SRS ]    NM_004994 [ ENTREZ ]
    RefSeqAC_000063 [ SRS ]    AC_000063 [ ENTREZ ]
    RefSeqAC_000152 [ SRS ]    AC_000152 [ ENTREZ ]
    RefSeqNC_000020 [ SRS ]    NC_000020 [ ENTREZ ]
    RefSeqNT_011362 [ SRS ]    NT_011362 [ ENTREZ ]
    RefSeqNW_001838666 [ SRS ]    NW_001838666 [ ENTREZ ]
    RefSeqNW_927339 [ SRS ]    NW_927339 [ ENTREZ ]
    AceViewMMP9 AceView - NCBI
    UnigeneHs.297413 [ SRS ]    Hs.297413 [ NCBI ]     HS297413 [ spliceNest ]
    Fast-db12552 (alternative variants)
    Protein : pattern, domain, 3D structure
    SwissProtP14780 [ SRS]    P14780 [ EXPASY ]     P14780 [ INTERPRO ]     P14780 [ UNIPROT ]
    PrositePS00546 CYSTEINE_SWITCH [ SRS ]    PS00546 CYSTEINE_SWITCH [ Expasy ]
    PrositePS00023 FN2_1 [ SRS ]    PS00023 FN2_1 [ Expasy ]
    PrositePS51092 FN2_2 [ SRS ]    PS51092 FN2_2 [ Expasy ]
    PrositePS00024 HEMOPEXIN [ SRS ]    PS00024 HEMOPEXIN [ Expasy ]
    PrositePS00142 ZINC_PROTEASE [ SRS ]    PS00142 ZINC_PROTEASE [ Expasy ]
    InterproIPR000562 FN_type2_col_bd [ SRS ]    IPR000562 FN_type2_col_bd [ EBI ]
    InterproIPR000585 Hemopexin [ SRS ]    IPR000585 Hemopexin [ EBI ]
    InterproIPR001818 Pept_M10A_M12B [ SRS ]    IPR001818 Pept_M10A_M12B [ EBI ]
    InterproIPR006025 Pept_M_Zn_BS [ SRS ]    IPR006025 Pept_M_Zn_BS [ EBI ]
    InterproIPR006026 Peptidase_M [ SRS ]    IPR006026 Peptidase_M [ EBI ]
    InterproIPR002477 Peptidoglycan-bd-like [ SRS ]    IPR002477 Peptidoglycan-bd-like [ EBI ]
    InterproIPR006970 PT [ SRS ]    IPR006970 PT [ EBI ]
    CluSTrP14780
    PfamPF00040 fn2 [ SRS ]    PF00040 fn2 [ Sanger ]    pfam00040 [ NCBI-CDD ]
    PfamPF00045 Hemopexin [ SRS ]    PF00045 Hemopexin [ Sanger ]    pfam00045 [ NCBI-CDD ]
    PfamPF00413 Peptidase_M10 [ SRS ]    PF00413 Peptidase_M10 [ Sanger ]    pfam00413 [ NCBI-CDD ]
    PfamPF01471 PG_binding_1 [ SRS ]    PF01471 PG_binding_1 [ Sanger ]    pfam01471 [ NCBI-CDD ]
    PfamPF04886 PT [ SRS ]    PF04886 PT [ Sanger ]    pfam04886 [ NCBI-CDD ]
    SmartSM00059 FN2 [EMBL]
    SmartSM00120 HX [EMBL]
    SmartSM00235 ZnMc [EMBL]
    ProdomPD000995 FN_Type_II[INRA-Toulouse]
    ProdomP14780 MMP9_HUMAN [ Domain structure ]   P14780 MMP9_HUMAN  [ sequences sharing at least 1 domain ]
    BlocksP14780
    PDB1GKC [ SRS ]    1GKC [ PdbSum ],   1GKC [ IMB ]   1GKC [ RSDB ]
    PDB1GKD [ SRS ]    1GKD [ PdbSum ],   1GKD [ IMB ]   1GKD [ RSDB ]
    PDB1ITV [ SRS ]    1ITV [ PdbSum ],   1ITV [ IMB ]   1ITV [ RSDB ]
    PDB1L6J [ SRS ]    1L6J [ PdbSum ],   1L6J [ IMB ]   1L6J [ RSDB ]
    PDB1LKG [ SRS ]    1LKG [ PdbSum ],   1LKG [ IMB ]   1LKG [ RSDB ]
    PDB2OVX [ SRS ]    2OVX [ PdbSum ],   2OVX [ IMB ]   2OVX [ RSDB ]
    PDB2OVZ [ SRS ]    2OVZ [ PdbSum ],   2OVZ [ IMB ]   2OVZ [ RSDB ]
    PDB2OW0 [ SRS ]    2OW0 [ PdbSum ],   2OW0 [ IMB ]   2OW0 [ RSDB ]
    PDB2OW1 [ SRS ]    2OW1 [ PdbSum ],   2OW1 [ IMB ]   2OW1 [ RSDB ]
    PDB2OW2 [ SRS ]    2OW2 [ PdbSum ],   2OW2 [ IMB ]   2OW2 [ RSDB ]
    HPRD00387
    Protein Interaction databases
    DIPP14780
    IntActP14780
    Polymorphism : SNP, mutations, diseases
    OMIM120361;603932    [ map ]   
    GENECLINICS120361;603932
    SNPMMP9 [dbSNP-NCBI]  
    SNPNM_004994 [SNP-NCI]  
    SNPMMP9 [GeneSNPs - Utah]  MMP9] [HGBASE - SRS]
    HAPMAPMMP9 [HAPMAP]  
    COSMICMMP9 [Somatic mutation (COSMIC-CGP-Sanger)]  
    HGMDMMP9
    General knowledge
    Family BrowserMMP9 [UCSC Family Browser]
    SOURCENM_004994
    SMDHs.297413
    SAGEHs.297413
    Enzyme3.4.24.35 [ Enzyme-Expasy ]   3.4.24.35 [ Enzyme-SRS ]   3.4.24.35 [ IntEnz-EBI ]   3.4.24.35 [ BRENDA ]   3.4.24.35 [ KEGG ]   3.4.24.35 [ WIT ]
    GOskeletal development [Amigo]  skeletal development
    GOgelatinase B activity [Amigo]  gelatinase B activity
    GOcalcium ion binding [Amigo]  calcium ion binding
    GOcollagen binding [Amigo]  collagen binding
    GOextracellular region [Amigo]  extracellular region
    GOproteinaceous extracellular matrix [Amigo]  proteinaceous extracellular matrix
    GOextracellular space [Amigo]  extracellular space
    GOproteolysis [Amigo]  proteolysis
    GOcollagenase activity [Amigo]  collagenase activity
    GOmetabolic process [Amigo]  metabolic process
    GOzinc ion binding [Amigo]  zinc ion binding
    GOextracellular matrix organization and biogenesis [Amigo]  extracellular matrix organization and biogenesis
    GOmacrophage differentiation [Amigo]  macrophage differentiation
    GOcollagen catabolic process [Amigo]  collagen catabolic process
    GOpositive regulation of apoptosis [Amigo]  positive regulation of apoptosis
    BIOCARTAInhibition of Matrix Metalloproteinases    [Genes]
    KEGGLeukocyte transendothelial migration
    PubGeneMMP9
    TreeFamMMP9
    CTD4318 [Comparative ToxicoGenomics Database]
    Other databases
    Probes
    ProbeMMP9 Related clones (RZPD - Berlin)
    PubMed
    PubMed499 Pubmed reference(s) in LocusLink

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    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written02-2006Deepak Pralhad Patil, Gopal Chandra Kundu

    Citation

    This paper should be referenced as such :
    Patil DP, Kundu GC . MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)). Atlas Genet Cytogenet Oncol Haematol. February 2006 .
    URL : http://AtlasGeneticsOncology.org/Genes/MMP9ID41408ch20q11.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon Aug 11 21:15:28 2008


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