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FLASH GENE
Symbol MMP14 contributors: mct - updated : 22-10-2016
HGNC name matrix metalloproteinase 14 (membrane-inserted)
HGNC id 7160
Corresponding disease
WINCH2 Winchester syndrome 2
Location 14q11.2      Physical location : 23.305.792 - 23.316.802
Synonym name
  • membrane type 1 metalloprotease
  • membrane-type matrix metalloproteinase 1
  • membrane-type-1 matrix metalloproteinase
    • Synonym symbol(s) MAP14, MTMMP1, MT1-MMP, MMPX1, MMP-X1
    EC.number 3.4.24.80
    DNA
    TYPE functioning gene
    SPECIAL FEATURE
    text member of the MMP cluster
    STRUCTURE 11.01 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure at the 5' putative regulatory elements including one SP1 site and four CCAAT boxes, promoter with distinctive structure
    MAPPING cloned Y linked   status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 3558 - 582 - 2005 16219679
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtongue  highly
     pharynx   highly
    Endocrinethyroid   highly
    Reproductivemale systemtestis    Rattus norvegicusFetal
    Respiratoryrespiratory tractlarynx  highly
    Skeleton breast    Mus musculus
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Reproductivegerm cell Rattus norvegicusFetal
    Skeletonosteoblast Mus musculus
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four hemoplexin-like domains
  • an extracellular domain connected to extracellular matrix, while its intracellular domain is a strong modulator of cell signaling
    • conjugated MetalloP
    isoforms Precursor cleaved by a furin endopeptidase
    HOMOLOGY
    interspecies homolog to murine Mmp14 (96.2pc)
    homolog to rattus Mmp14 (96.7pc)
    Homologene
    FAMILY
  • peptidase M10A family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
    basic FUNCTION
  • regulator of matrix remodeling
  • initiating pro-MMP2 activation by a process tightly regulated by TIMP2
  • activating MMP13
  • participates in kidney tubulogenesis and epithelial cells migration
  • having a role in reduced cell adhesion and spreading
  • catalyzing the cleavage of APP
  • mediating MUC1 shedding independent of ADAM17
  • degrades the extracellular matrix, initiates the activation pathway of soluble MMPs and regulates the functionality of cell adhesion signaling receptors, thus playing an important role in many cell functions
  • cleaving MMP14, directly, rather than indirectly
  • with TIMP2, control cell proliferation and migration through a non-proteolytic mechanism
  • role for MMP14/TIMP-2 interaction, in controling cell functions by a mechanism independent of extracellular matrix degradation
  • activating MMP2 on the tumor cell surface and thus may be involved in tumor invasion
  • involved in endothelial cell tubulogenesis during vascular morphogenesis
  • master regulator of the pathologic extracellular matrix remodeling that characterizes rheumatoid arthritis as well as the coupled angiogenic response that maintains the aggressive phenotype of the advancing pannus
  • cleaving BCAM (Lu protein)
  • plays a required role in mesenchymal stem cell-mediated collagenolysis, 3D invasion and intravasation
  • plays a role in both inflammation and the onset of multiple sclerosis and, potentially, other neuroimmune diseases
  • membrane-anchored metalloproteinase that mediates pericellular proteolysis of a wide range of extracellular matrix proteins including type-I collagen
  • zinc-dependent type-I transmembrane metalloproteinase involved in pericellular proteolysis, migration and invasion
  • regulates KDR cell surface localisation and forms a complex with KDR and SRC that is dependent on the MMP14 hemopexin domain and independent of its catalytic activity
  • promotes macrophage migration in a non-proteolytic manner
  • having APBA3-dependent and APBA3-independent activities (APBA3-dependent mechanism represents the effect of MMP14 on ATP production in macrophages)
  • MMP14 and MMP19 are proteolytic enzymes potentially involved in aneurysm formation in the ascending aorta of patients with tricuspid aortic valves
  • crucial regulator of fibronectin turnover
  • regulates ECM fibronectin remodeling by promoting extracellular cleavage of fibronectin and by regulating ITGA5/B1-integrin endocytosis
  • plays a role in osteocyte mechanosensing by affecting the osteocyte response to mechanical loading
  • regulating HIF-mediated chemokine/cytokine gene transcription within niche cells
  • its expression in keratinocytes is dispensable for skin homeostasis and repair, but plays a crucial role in the epidermal-dermal crosstalk leading to modulation of vessel density
  • membrane-tethered metalloproteinase MMP14, capable of remodeling the extracellular matrix and modulating receptors on the cell surface
  • MMP14 and MMP19 have been demonstrated to play an important role in the development of human gliomas
  • functions in part as a pericellular activator of MMP2
  • is the only MT-MMP that contributes to soluble endoglin production in pre-eclampsia
  • play an important role in invasion and metastasis of human solid tumor
  • prevents growth inhibition by three dimensional fibronectin matrix
  • may play role in regulating angiogenesis in human endothelial cells
    • CELLULAR PROCESS cell migration & motility
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    central pathway involving MMP14 and TGFbeta that mediates vessel stability and vascular response to tissue injury
    a component
  • forms a complex with FGFR2 and ADAM9 in osteoblasts
    • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Ca2+
  • Zn2+
    • protein
  • interacting with BSGN
  • CLDN5
  • MMP2
  • CSF2
  • NANOS1, by regulating MMP14 expression, plays an important role in the acquisition of invasive properties by epithelial tumor cells
  • binding TIMPs in a 1:1 stoechiometry, stimulating invasion-promoting MEK/ERK signaling in cancer cells
  • binds tissue inhibitor of metalloproteinases-2 (TIMP2), activates matrix metalloproteinase-2 (MMP2), and stimulates cell migration in various cell types
  • MMP14 and FURIN were found to co-localize with Golgi reassembly stacking protein 55 (GORASP2)
  • interacting with CD9 (CD9 appears to, at least in part, contribute to the delocalization of integrins and MMP14, disruption of which may prevent angiogenesis)
  • activates HIF1A via APBA3 in many types of cell so as to stimulate glycolysis
  • inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface
  • in actively invading cells, WASL promoted trafficking of MMP14 into invasive pseudopodia, primarily from late endosomes, from which it was delivered to the plasma membrane
  • direct interactions between cellular MMP14 and PTK7 that constitute an evolutionary conserved master switch in directional cell motility
  • TACR1 was a potential regulator of human glioma cell migration by the up-regulation of MMP2 and MMP14
  • MMP14 cleaved EPHA2 at its Fibronectin type-III domain 1
  • MMP14 is an up-stream regulator for MMP2 and TIMP2 expression
  • WASH1 and exocyst are required for matrix degradation by an exocytic mechanism that involves tubular connections between MMP14–positive late endosomes and the plasma membrane in contact with the matrix
  • MMP14 proteolysis of BRCA2 regulates the abundance of BRCA2 on centrosomes
  • CD81 stimulates melanoma cell motility by inducing MMP14 expression through the AKT1-dependent Sp1 activation signaling pathway, leading to increased melanoma invasion and metastasis
  • TGFB1I1 appears to enhance complex formation between MMP14 and PTK2 in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility
  • MMP14 inhibits the tetherin activity of BST2 by interacting with BST2, and the cytoplasmic domains of both BST2 and MMP14 play critical roles within this interaction
    • cell & other
    REGULATION
    activated by furin (intracellularly) and proteinases
    inhibited by prolonged or reduced hypoxia
    TFPI2
    RECK
    Other TIMP2,promoting the availability of active MMP14 and active pericellular proteolysis,inhibiting MMP14 autocatalysis to the 44kDa form
    regulated by claudin
    regulated on the cell surface through a vacuolar H(+)-ATPase-dependent degradation process
    ASSOCIATED DISORDERS
    corresponding disease(s) WINCH2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in oral squamous cell carcinoma (OSCC) with lymph node metastasis
    constitutional     --over  
    in keratoconus cornea
    tumoral       gain of function
    in head and neck cancer (by CSF2)and in melanoma in progression
    tumoral     --over  
    in glioma-associated microglia
    constitutional     --over  
    reduced corneal opacity and expression of the major genes involved in corneal scarring, especially type III collagen and alpha-smooth muscle actin
    tumoral     --over  
    in human gastric cancer and its association with tumor progression
    Susceptibility to chronic obstructive pulmonary
    Variant & Polymorphism other haplotype -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of chronic obstructive pulmonary disease
    Candidate gene
  • tyrosine-phosphorylated MMP14 plays an important role in neuroblastoma progression and its expression is preferentially observed in tumor specimens from neuroblastoma patients showing poor clinical outcome
    • Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerbrain 
    targeted inhibition of MMP14 or SLC37A4 may lead to reduced infiltrative and invasive properties of brain tumor cells
    ANIMAL & CELL MODELS
  • Mt1-Mmp-/- mice had a lower number of empty lacunae and a higher osteocyte density