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

Identity

Other namesCLG4B
GELB
MANDP2
MMP-9
HGNC (Hugo) MMP9
LocusID (NCBI) 4318
Atlas_Id 41408
Location 20q13.12
Location_base_pair Starts at 44637547 and ends at 44645200 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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
    HGNC (Hugo)MMP9   7176
    Cards
    AtlasMMP9ID41408ch20q11
    Entrez_Gene (NCBI)MMP9  4318  matrix metallopeptidase 9
    GeneCards (Weizmann)MMP9
    Ensembl hg19 (Hinxton)ENSG00000100985 [Gene_View]  chr20:44637547-44645200 [Contig_View]  MMP9 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000100985 [Gene_View]  chr20:44637547-44645200 [Contig_View]  MMP9 [Vega]
    ICGC DataPortalENSG00000100985
    TCGA cBioPortalMMP9
    AceView (NCBI)MMP9
    Genatlas (Paris)MMP9
    WikiGenes4318
    SOURCE (Princeton)MMP9
    Genomic and cartography
    GoldenPath hg19 (UCSC)MMP9  -     chr20:44637547-44645200 +  20q13.12   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)MMP9  -     20q13.12   [Description]    (hg38-Dec_2013)
    EnsemblMMP9 - 20q13.12 [CytoView hg19]  MMP9 - 20q13.12 [CytoView hg38]
    Mapping of homologs : NCBIMMP9 [Mapview hg19]  MMP9 [Mapview hg38]
    OMIM120361   613073   
    Gene and transcription
    Genbank (Entrez)AK298246 AK301446 AK302530 AK303080 AK311648
    RefSeq transcript (Entrez)NM_004994
    RefSeq genomic (Entrez)NC_000020 NC_018931 NG_011468 NT_011362 NW_004929418
    Consensus coding sequences : CCDS (NCBI)MMP9
    Cluster EST : UnigeneHs.297413 [ NCBI ]
    CGAP (NCI)Hs.297413
    Alternative Splicing : Fast-db (Paris)GSHG0018796
    Alternative Splicing GalleryENSG00000100985
    Gene ExpressionMMP9 [ NCBI-GEO ]     MMP9 [ SEEK ]   MMP9 [ MEM ]
    SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP14780 (Uniprot)
    NextProtP14780  [Medical]  [Publications]
    With graphics : InterProP14780
    Splice isoforms : SwissVarP14780 (Swissvar)
    Catalytic activity : Enzyme3.4.24.35 [ Enzyme-Expasy ]   3.4.24.353.4.24.35 [ IntEnz-EBI ]   3.4.24.35 [ BRENDA ]   3.4.24.35 [ 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)FN_type2_col-bd    Hemopexin-like_dom    Hemopexin-like_repeat    Hemopexin_CS    Kringle-like    MetalloPept_cat_dom    MMP9    Pept_M10_metallopeptidase    Pept_M10A    Pept_M10A_Zn_BS    Peptidase_Metallo    Peptidoglycan-bd-like    PT   
    Related proteins : CluSTrP14780
    Domain families : Pfam (Sanger)fn2 (PF00040)    Hemopexin (PF00045)    Peptidase_M10 (PF00413)    PG_binding_1 (PF01471)    PT (PF04886)   
    Domain families : Pfam (NCBI)pfam00040    pfam00045    pfam00413    pfam01471    pfam04886   
    Domain families : Smart (EMBL)FN2 (SM00059)  HX (SM00120)  ZnMc (SM00235)  
    DMDM Disease mutations4318
    Blocks (Seattle)P14780
    PDB (SRS)1GKC    1GKD    1ITV    1L6J    1LKG    2OVX    2OVZ    2OW0    2OW1    2OW2    4H1Q    4H2E    4H3X    4H82    4HMA    4JIJ    4JQG   
    PDB (PDBSum)1GKC    1GKD    1ITV    1L6J    1LKG    2OVX    2OVZ    2OW0    2OW1    2OW2    4H1Q    4H2E    4H3X    4H82    4HMA    4JIJ    4JQG   
    PDB (IMB)1GKC    1GKD    1ITV    1L6J    1LKG    2OVX    2OVZ    2OW0    2OW1    2OW2    4H1Q    4H2E    4H3X    4H82    4HMA    4JIJ    4JQG   
    PDB (RSDB)1GKC    1GKD    1ITV    1L6J    1LKG    2OVX    2OVZ    2OW0    2OW1    2OW2    4H1Q    4H2E    4H3X    4H82    4HMA    4JIJ    4JQG   
    Human Protein AtlasENSG00000100985
    Peptide AtlasP14780
    HPRD00387
    IPIIPI00027509   IPI00922121   
    Protein Interaction databases
    DIP (DOE-UCLA)P14780
    IntAct (EBI)P14780
    FunCoupENSG00000100985
    BioGRIDMMP9
    IntegromeDBMMP9
    STRING (EMBL)MMP9
    Ontologies - Pathways
    QuickGOP14780
    Ontology : AmiGOskeletal system development  ossification  positive regulation of protein phosphorylation  endopeptidase activity  metalloendopeptidase activity  protein binding  collagen binding  extracellular region  proteinaceous extracellular matrix  extracellular space  proteolysis  axon guidance  embryo implantation  metallopeptidase activity  zinc ion binding  extracellular matrix disassembly  extracellular matrix organization  macrophage differentiation  collagen catabolic process  endodermal cell differentiation  identical protein binding  negative regulation of apoptotic process  positive regulation of DNA binding  positive regulation of epidermal growth factor receptor signaling pathway  ephrin receptor signaling pathway  leukocyte migration  positive regulation of keratinocyte migration  extracellular exosome  positive regulation of release of cytochrome c from mitochondria  positive regulation of receptor binding  negative regulation of intrinsic apoptotic signaling pathway  negative regulation of cation channel activity  negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway  
    Ontology : EGO-EBIskeletal system development  ossification  positive regulation of protein phosphorylation  endopeptidase activity  metalloendopeptidase activity  protein binding  collagen binding  extracellular region  proteinaceous extracellular matrix  extracellular space  proteolysis  axon guidance  embryo implantation  metallopeptidase activity  zinc ion binding  extracellular matrix disassembly  extracellular matrix organization  macrophage differentiation  collagen catabolic process  endodermal cell differentiation  identical protein binding  negative regulation of apoptotic process  positive regulation of DNA binding  positive regulation of epidermal growth factor receptor signaling pathway  ephrin receptor signaling pathway  leukocyte migration  positive regulation of keratinocyte migration  extracellular exosome  positive regulation of release of cytochrome c from mitochondria  positive regulation of receptor binding  negative regulation of intrinsic apoptotic signaling pathway  negative regulation of cation channel activity  negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway  
    Pathways : BIOCARTAInhibition of Matrix Metalloproteinases [Genes]   
    Pathways : KEGGTNF signaling pathway    Leukocyte transendothelial migration    Estrogen signaling pathway    Hepatitis B    Pathways in cancer    Transcriptional misregulation in cancer    Proteoglycans in cancer    MicroRNAs in cancer    Bladder cancer   
    REACTOMEP14780 [protein]
    REACTOME PathwaysREACT_118779 Extracellular matrix organization [pathway]
    REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
    Protein Interaction DatabaseMMP9
    DoCM (Curated mutations)MMP9
    Wikipedia pathwaysMMP9
    Gene fusion - Rearrangements
    Gene fusion: TCGA
    Polymorphisms : SNP, variants
    NCBI Variation ViewerMMP9 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)MMP9
    dbVarMMP9
    ClinVarMMP9
    1000_GenomesMMP9 
    Exome Variant ServerMMP9
    SNP (GeneSNP Utah)MMP9
    SNP : HGBaseMMP9
    Genetic variants : HAPMAPMMP9
    Genomic Variants (DGV)MMP9 [DGVbeta]
    Mutations
    ICGC Data PortalMMP9 
    TCGA Data PortalMMP9 
    Tumor PortalMMP9
    Somatic Mutations in Cancer : COSMICMMP9 
    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
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)20:44637547-44645200
    CONAN: Copy Number AnalysisMMP9 
    Mutations and Diseases : HGMDMMP9
    OMIM120361    613073   
    MedgenMMP9
    NextProtP14780 [Medical]
    GENETestsMMP9
    Disease Genetic AssociationMMP9
    Huge Navigator MMP9 [HugePedia]  MMP9 [HugeCancerGEM]
    snp3D : Map Gene to Disease4318
    DGIdb (Drug Gene Interaction db)MMP9
    BioCentury BCIQMMP9
    General knowledge
    Homologs : HomoloGeneMMP9
    Homology/Alignments : Family Browser (UCSC)MMP9
    Phylogenetic Trees/Animal Genes : TreeFamMMP9
    Chemical/Protein Interactions : CTD4318
    Chemical/Pharm GKB GenePA30889
    Clinical trialMMP9
    Cancer Resource (Charite)ENSG00000100985
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineMMP9
    GoPubMedMMP9
    iHOPMMP9

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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. 2006;10(3):168-170.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/MMP9ID41408ch20q11.html

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    indexed on : Sat Jun 27 14:54:36 CEST 2015

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