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FLASH GENE
Symbol MMP9 contributors: mct/pgu - updated : 24-04-2017
HGNC name matrix metalloproteinase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)
HGNC id 7176
Corresponding disease
MAND1 metaphyseal anadysplasia 1
Location 20q13.12      Physical location : 44.637.546 - 44.645.199
Synonym name
  • 92 kDa gelatinase
  • gelatinase B
  • type V collagenase
  • Synonym symbol(s) CLG4B, MMP-9, GELB, MANDP2
    EC.number 3.4.24.35
    DNA
    TYPE functioning gene
    STRUCTURE 7.65 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site   transcription factor
    text structure
  • consensus binding sequence for NFKB and the activation of NFKB is prerequisite for the expression of MMP9 in response to various catabolic stimuli
  • FOSL1 occupy regions of the MMP9 promoter in trophoblast cells critical for the regulation of MMP9 gene expression
  • a potential Stat3 binding site, just juxtaposed AP-1 consensus sequence (activation of MMP9 promoter is dependent upon interactions of FOSL1/c-Jun with STAT3)
  • KLF8 directly bound and activated the human MMP9 gene promoter
  • MAPPING cloned Y linked Y status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 2387 78.3 707 - 1992 1281792
    - - - 82 - expressed on the surface of malignant cells 2007 17489740
  • also called 82 pro-MMP9
  • may escape inhibition by natural TIMP1, thereby facilitating cellular invasion
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     mouthtongue  highly
    Lymphoid/Immunespleen   highly
     thymus   highly
     tonsils   highly
    Nervousbrainlimbic systemhippocampus highly Homo sapiensAdult
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connective    
    cells
    SystemCellPubmedSpeciesStageRna symbol
     mast cell
    Blood/Hematopoieticgranulocyte
    Cardiovascularendothelial cell
    Lymphoid/Immunemacrophage
    not specificchondrocyte
    Skeletonosteoclast
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a signal sequence
  • a unique CBD (collagen-binding domain) containing three fibronectin type II-like modules
  • a prodomain with cysteine residue, essential for latency
  • a hinge region
  • a C terminal hemopexin-like domain with integrin binding activity, that is a prerequisite for enhanced cell migration
  • conjugated HemoP , MetalloP
    mono polymer homomer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • MMP family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION extracellular
    text
  • extracellular matrix
  • is secreted as a latent pro-enzyme that requires activation in the extracellular space
  • basic FUNCTION
  • regulator of matrix remodeling
  • playing a significant role in tumour invasion and angiogenesis
  • highly involved in early embryo implantation
  • codes for an enzyme engaged in the regulation of neuronal plasticity and can also contribute to neuronal cell death in pathological conditions
  • MMP9 and MMP12 promote intimal thickening by independent cleavage of N-cadherin, which elevates vascular smooth muscle cell proliferation via beta-catenin signalling
  • associated with neovascularization
  • generating angiostatin fragments by hydrolyzing plasminogen
  • also involved in the migratory process (acute and chronic inflammation of tumoral metastatic process and in injury processus of myofibers)
  • playing a control role of keratinocyte growth
  • involved in enhanced collagen affinity, reduced IL-2 response
  • pro/antiinflammatory roles
  • may act not only as a solubilizer of bone matrix but also as a regulator of initiation of bone resorption and coupling to bone formation
  • with MMP13 play a role in endochondral ossification
  • involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis
  • initiates cross-talk between CD44 and EGFR, which in turn activates downstream effectors for cell migration
  • NEU1 and MMP9 in complex with TLR receptors at the ectodomain form a molecular organizational signaling platform on the cell surface that is essential for ligand activation of TLR receptors and cellular signaling
  • extracellularly acting, Zn(2+)-dependent endopeptidase, that is important not only for pathologies of the central nervous system but also for neuronal plasticity
  • is functionally involved in synaptic remodelling
  • novel effector which is required for Neural Crest Cells delamination and migration
  • regulates survival of neurons by regulating laminin-integrin beta1 signaling during developmental neuronal death
  • role for MMP9 in regulating neuronal survival through the developmental process that establishes the functional brain
  • plays a major role in regulating laminin levels in neonatal hippocampus
  • extracellular matrix proteolytic protease, playing an important role in epileptogenesis
  • converts proBDNF to mature BDNF and may play a role in the pathophysiology of major depressive disorder
  • plays a critical role in regulation of spine morphology and synaptic plasticity
  • key enzyme for the degradation of extracellular matrix in aneurysm walls
  • CELLULAR PROCESS cell life, proliferation/growth
    cell migration & motility
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • among secreted MMPs, only MMP9 is capable of forming a homodimer
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • binding TIMPs in a 1:1 stoechiometry
  • interacting with PGF (PGF/MMP9 expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle)
  • interacting with KLF5 (causes cartilage matrix degradation through transcriptional induction of MMP9, providing the first evidence that transcriptional regulation of a proteinase contributes to endochondral ossification and skeletal development)
  • interacting with EGR1 (directly binds to the MMP9 promoter and plays an essential role for TNF1 induction of MMP9 transcription)
  • bind to several cell surface receptors including CD44, LRP1, LRP2
  • MMP9 expression induced by TGFA is a valid target of PPARD ligands in keratinocytes
  • ITGB4 associates with MMP9 and its ectodomain is a target for cleavage by MMP9
  • PLG regulates MMP9-dependent CXCR4 expression to facilitate hematopoietic progenitor and stem cell (HPSC) mobilization in response to CSF3
  • CREB3 plays a critical role in MMP9 expression and is probably involved in invasion and metastasis of cervical cancer
  • SMYD3 is an important new regulator of MMP9 transcription, providing a molecular link between SMYD3 overexpression and metastatic cancer progression
  • MMP9 is a gene tightly regulated by the MXI1 gene
  • induce the expression of MMP9 in macrophages, and MMP9 is known to be essential for tumor cell migration and invasion
  • TNF promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression
  • ADAM10 and/or MMP9 are playing important roles in constitutive and PACAP-induced RAGE shedding
  • regulator of ERBB2 expression on human mammary epithelial cells
  • MMP9 cleaved NINJ1 in between Leu56 and Leu57 on its N-terminal ectodomain
  • MMP9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of IAPP
  • MTOR signaling is important to regulate the expression, activity and secretion of matrix metalloproteinases MMP9
  • ADAM17 mediates MMP9 expression in lung epithelial cells
  • NUMBL could decrease the expression of TRAF6, CCND1, and MMP9 and increase the expression of CASP3
  • NFATC1 sequestering the SMAD3 prevents the proteasome mediated degradation of SKIL and SKIL has a role on the regulation of MMP2, MMP9 activity
  • HDAC10 binds to the promoter regions of MMP2 and -9, deacetylates histones H3 and H4 in these regions, blocks the binding of RNA polymerase II, and consequently down-regulates MMP2 and -9 expression
  • LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
  • MMP9 enhances PRKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound VEGFA, increasing its bioavailability and angiogenesis
  • MMP9 inhibits IL23A expression in dendritic cells by targeting membrane stem cell factor affecting lung IL17 response
  • RAC1 controls surface mobilization of CD40LG on activated platelets and MMP9 secretion from neutrophils
  • MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells
  • recruitment of MMP9 to the fibroblast cell surface occurs through its fibronectin-like (FN) domain and the molecule responsible for the recruitment is PLOD3
  • CTSK was responsible for the activation of pro-MMP9, with a key link between CTSK expression in tumors and bone and ECM remodeling, through MMP9 activation
  • PGF may activate MMP9 via MAPK14 signaling pathway
  • MMP9 is active in islets and cleaves IAPP
  • CA8 might facilitate cancer cell invasion via the activation of PTK2-MMP9 signaling
  • expression of MMP9 was enhanced with an upregulation of HOXC6 expression while HOXC6 downregulation lowered MMP9 gene expression levels
  • INVS could upregulate the expression of CDH2, VIM, MMP2, and MMP9
  • overexpression of GADD45A activated MMP9 expression by inducing promoter demethylation
  • cell & other
    REGULATION
    activated by NRG1 isoform beta_1 in breast cancer
    proteinases and plasmin
    KLF8 (its overexpression induced a strong increase in MMP9 expression and activity)
    induced by FOXO3
    STAT3 and AP-1 (functional cooperation of the STAT3 and AP-1 transcription factors is required for the transcription of MMP9 gene)
    inhibited by TIMPs and TFPI2
    RECK
    irisolidone
    repressed by YY1 in neurons
    Other regulated by S100A4 in prostate carcinoma cells
    regulated by nucleolin (role in posttranscriptional control of MMP9 expression)
    ASSOCIATED DISORDERS
    corresponding disease(s) MAND1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in cutaneous squamous cell carcinoma with metastatic potential and in in sporadic colorectal cancer
    tumoral     --low  
    in diffuse type gastric carcinoma, and in hereditary non-polyposis colorectal carcinoma
    tumoral     --over  
    in breast cancer and in prostate cancer with aggressive phenotype
    constitutional       gain of function
    in chronic obstructive pulmonary disease
    constitutional     --over  
    at the site of abdominal aortic aneurysm rupture
    constitutional     --over  
    in arthritis, degrading non-collagen matrix components of the joints
    constitutional     --over  
    higher in MADYS1 (mandibuloacral dysplasia type A) sera compared with healthy controls
    constitutional     --over  
    in skeletal muscle tissues after nerve injury, heart failure and inflammatory myopathy, and exacerbate dystrophinopathy by augmenting fiber necrosis, ECM degradation, inflammation and fibrosis
    tumoral     --over  
    is associated with accumulation of the pleural effusion in malignancy
    constitutional     --over  
    hypertension-induced atherosclerosis was associated with significantly increased levels of MMP9 mRNA, which may enhance both the deposition of types I and III collagen and atherosclerotic plaque formation
    constitutional     --over  
    may be linked with the intractable epilepsy caused by focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC)
    constitutional       gain of function
    SPARC, MMP2 and MM9 were significantly up-regulated in intracranial aneurysms relative to the expression levels in the normal Circle of Willis arteries
    constitutional     --low  
    AHSG, MMP9, and MMP3 levels were significantly lower in migraine than controls
    tumoral     --over  
    in the invasive group of pituitary adenomas (pMID: 21279695)
    Susceptibility
  • to dementia
  • to toxic epidermal necrolysis and to Stevens-Johnson syndrome
  • to lumbar-disc herniation
  • to exudative form of age-related macular degeneration (AMD)
  • to cleft lip/palate
  • to inflammatory bowel diseases
  • to polymyositis
  • to malignant gliomas
  • to coronary atherosclerosis, and to carotid arteries atherosclerosis
  • to macroangiopathic complications in type 2 diabetes mellitus (T2DM)
  • to multiple sclerosis (MS)
  • Variant & Polymorphism repeat , other
  • polymorphism 1562c>t having protective effect against dementia
  • longer microsatellites in the promoter of MMP9 are associated to the exudative form of AMD
  • (> or =22 CA) in the microsatellite of the promoter, is associated to carotid atherosclerosis
  • frequency of the allele T was higher in patients with macroangiopathic complications in type 2 diabetes mellitus (T2DM)
  • MMP9 C(-1562)T and (CA)(n) polymorphisms contribute to multiple sclerosis (MS)
  • Candidate gene
    Marker
  • measurement of serum MMP9 might be clinically useful for pancreatic ductal adenocarcinoma diagnosis
  • potential DMD biomarker for disease progression
  • urinary MMP9/LCN2 and ADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease
  • Therapy target
    SystemTypeDisorderPubmed
    immunologyautoimmune 
    target for therapy of autoimmune diseases
    neuromuscularmyopathydegenerative
    PGF–MMP9–expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle
    cancerbrainglioma/neuroblstoma
    inhibition by irisolidone might be a potential therapeutic modality for controlling the growth and invasiveness of gliomas
    neuromuscularmyopathydegenerative
    one of the most promising therapeutic targets for the prevention of disease progression in DMD
    neurosensorialvisualanterior chamber
    potential therapeutic targets (MMP-9) against proliferative vitreoretinopathy (PVR)
    diabetetype 2 
    increasing islet MMP9 activity might be a strategy to limit beta-cell loss in type 2 diabetes
    ANIMAL & CELL MODELS
  • key regulator of grow plate angiogenesis and apoptosis of hypertrophic chondrocytes in mice
  • Deletion of Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation and fiber necrosis