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

2006-02-01   Deepak Pralhad Patil , Gopal Chandra Kundu 

National Center for Cell Science, NCCS Complex, Ganeshkhind, Pune 411007, India

Identity

HGNC
LOCATION
20q13.12
LOCUSID
ALIAS
CLG4B,GELB,MANDP2,MMP-9
FUSION GENES

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.

Proteins

Atlas Image
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 name
    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 name
    Arthritis, autosomal recessive osteolysis disorder, coronary artery disease, pulmonary-emphysema and diabetic retinopathy.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    121675812002Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials.Bloomston M et al
    84947111993Activity of type IV collagenases in benign and malignant breast disease.Davies B et al
    65253361984An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides.Hangauer DG et al
    113492152001The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.John A et al
    129528362003Matrix metalloproteinases as novel disease markers in Takayasu arteritis.Matsuyama A et al
    157579002005JNK1 differentially regulates osteopontin-induced nuclear factor-inducing kinase/MEKK1-dependent activating protein-1-mediated promatrix metalloproteinase-9 activation.Rangaswami H et al
    116874972001How matrix metalloproteinases regulate cell behavior.Sternlicht MD et al
    102259661999Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.Stetler-Stevenson WG et al
    106522712000Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.Yu Q et al
    103341901999Loss 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 et al

    Other Information

    Locus ID:

    NCBI: 4318
    MIM: 120361
    HGNC: 7176
    Ensembl: ENSG00000100985

    Variants:

    dbSNP: 4318
    ClinVar: 4318
    TCGA: ENSG00000100985
    COSMIC: MMP9

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000100985ENST00000372330P14780

    Expression (GTEx)

    0
    100
    200
    300
    400
    500
    600

    Pathways

    PathwaySourceExternal ID
    Leukocyte transendothelial migrationKEGGko04670
    Bladder cancerKEGGko05219
    Leukocyte transendothelial migrationKEGGhsa04670
    Pathways in cancerKEGGhsa05200
    Bladder cancerKEGGhsa05219
    Transcriptional misregulation in cancerKEGGko05202
    Transcriptional misregulation in cancerKEGGhsa05202
    Hepatitis BKEGGhsa05161
    Proteoglycans in cancerKEGGhsa05205
    Proteoglycans in cancerKEGGko05205
    Estrogen signaling pathwayKEGGhsa04915
    Estrogen signaling pathwayKEGGko04915
    TNF signaling pathwayKEGGhsa04668
    TNF signaling pathwayKEGGko04668
    MicroRNAs in cancerKEGGhsa05206
    MicroRNAs in cancerKEGGko05206
    Immune SystemREACTOMER-HSA-168256
    Innate Immune SystemREACTOMER-HSA-168249
    Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
    Signaling by InterleukinsREACTOMER-HSA-449147
    Signal TransductionREACTOMER-HSA-162582
    Signaling by SCF-KITREACTOMER-HSA-1433557
    Extracellular matrix organizationREACTOMER-HSA-1474244
    Collagen formationREACTOMER-HSA-1474290
    Assembly of collagen fibrils and other multimeric structuresREACTOMER-HSA-2022090
    Degradation of the extracellular matrixREACTOMER-HSA-1474228
    Activation of Matrix MetalloproteinasesREACTOMER-HSA-1592389
    Collagen degradationREACTOMER-HSA-1442490
    Developmental BiologyREACTOMER-HSA-1266738
    Axon guidanceREACTOMER-HSA-422475
    EPH-Ephrin signalingREACTOMER-HSA-2682334
    EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665
    Endocrine resistanceKEGGko01522
    Endocrine resistanceKEGGhsa01522
    Neutrophil degranulationREACTOMER-HSA-6798695
    Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
    IL-17 signaling pathwayKEGGko04657
    Fluid shear stress and atherosclerosisKEGGko05418
    IL-17 signaling pathwayKEGGhsa04657
    Fluid shear stress and atherosclerosisKEGGhsa05418

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    PharmGKB

    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA448871celecoxibChemicalPathwayassociated22336956

    References

    Pubmed IDYearTitleCitations
    122088632002Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms.284
    123988932002MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis.240
    235477852013Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade.186
    114860092001The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL.178
    128654052003HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver.147
    129609612003Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator.146
    126684892003Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease.145
    180773792007Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis.142
    118395882002Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells.140
    183234982008MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke.132

    Citation

    Deepak Pralhad Patil ; Gopal Chandra Kundu

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

    Atlas Genet Cytogenet Oncol Haematol. 2006-02-01

    Online version: http://atlasgeneticsoncology.org/gene/41408/mmp9