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MMP14 (matrix metallopeptidase 14 (membrane-inserted))

Identity

Other namesMMP-X1
MT1-MMP
MTMMP1
HGNC (Hugo) MMP14
LocusID (NCBI) 4323
Location 14q11.2
Location_base_pair Starts at 23305742 and ends at 23316808 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
Description MMP14 spans 11009 bp on chromosome 14 in the region of q11.2. It consists of 10 exons.
Transcription The human MMP-14 (MT1-MMP) transcript has been determined to be 3558 bp in length before splicing and 1749 bp after splicing. The start codon (ATG) of MMP-14 gene exists in the first exon and the stop codon (TGA) is present in the last and longest exon of the transcribed product of MMP-14. No TATA box, which controls the expression of 30% of all genes found in the human genome, is found in the proximal region in the MMP-14 promoter. In the promoter region, Egr-1 has been reported to be one of the most important transcription factors regulating the expression of MMP-14. MMP-14 expression is also regulated by other transcription factors, including AP-4, NF-kB, c-ETS1 and p53. However, some common transcription factors, such as AP-1, AP-2 and TGF-alpha, which play major roles in the regulation of other MMPs do not have binding sites within the promoter of MMP-14. Besides these common transcription factors, MMP-14 expression is also regulated by hypoxia inducible factor 2a (HIF-2alpha) under hypoxic conditions. Two HBSs (HIF binding site) have been identified in the proximal promoter region, the one around -125 bp relative to the transcription start site is shown to affect MMP-14 transcription. Some growth factors and cytokines, e.g IL1B, EGF, TNFalpha, bFGF, GM-CSF, SF/HGF, and TGF-beta have also been reported to induce the expression of MMP-14.
Two functional SNPs in the MMP-14 promoter have been found in focal-segmental glomerulosclerosis (FSGS) disease. -378 T/C and -364 G/T alterations cause a reduction in the expression of MMP-14 and correlate with significant risk reduction of FSGS. Epigenetic regulation is also involved in the regulation of MMP-14 expression. Hypermethylation of the CpG100 island, which spans a region from the proximal promoter to the 1st intron of MMP-14, and trimethylation of Histone H3 lysine-27 (known as a repressive marker) are determined as epigenetic controls causing the transcriptional silencing of MMP-14.
Pseudogene No pseudogenes have been identified.

Protein

 
  Schematic representation of the domain structures of MMP-14 (domains are not scaled).
Description Matrix metalloproteinases (MMPs) compose one of the metzincins super family also known as zinc endopeptidases. Highly conserved motif of this family contains three histidines that bind zinc ion in the catalytic site of the protein and conserved methionine. Besides the secreted MMPs of the MMP family, six membrane type-MMPs have been identified so far, all with similar domain compositions. The best characterized MT-MMP is MMP-14 or MT1-MMP, which contains seven domains from N-terminus to C-terminus: a signal peptide leading MMP-14 into the secretory pathway; a propeptide domain maintaining MMP in a latent form; a catalytic domain responsible for enzymatic activity; a hinge region maintaining proper conformation; a hemopexin domain required for substrate reorganization; a transmembrane domain anchoring MMP into the plasma membrane; and a cytoplasmic domain required for endocytosis. MT-1, MT2-, MT3- and MT5-MMPs all contain seven similar domains, whereas MT4- and MT6-MMPs lack the transmembrane and cytoplasmic domains. Both MT4- and MT6-MMPs are linked to the cell surface through GPI-anchorage. There is a furin consensus sequence (Arg108-Arg109-Lys110-Arg111) between MMP-14 propeptide and catalytic domains. Furin has been reported to be responsible for MMP-14 activation. However, the activation mechanism of MMP-14 is still under debate. The hemopexin-like domain of MMP-14 is the largest domain, and it provides a suitable flat surface for the protein-protein interactions with the existence of four bladed beta-propeller structures.
Expression MMP-14 is widely expressed in human tissues. Its expression has been proven in the adult human intestine, kidney, lung, ovary, placenta, prostate, and spleen. Increase in its expression level has also been observed in the wound healing area. A Mouse embryogenesis study provides evidence for the expression of MMP-14 mainly in the muscle cells, fibroblast, chondrocytes, and neural cells. MMP-14 is upregulated in most human cancers. Both cancer and stromal cells have been reported to be upregulated in tumor tissues.
Localisation Plasma Membrane (single-pass type I membrane protein). MMP-14 contains a 24 amino acid hydrophobic motif at the C-terminus which is responsible for plasma membrane localization of MMP-14.
Function MMP-14 plays an important role in remodelling of extracellular matrix (ECM) and enhancing cell migration. Besides the role of MMP-14 in these pathophysiological processes, it also plays an important physiological role during development. Studies performed with MMP-14 null mice have shown the importance of its function during embryogenesis as the lack of MMP-14 caused craniofacial dysmorphism, arthritis, osteopenia, dwarfism, fibrosis of soft tissues and premature death. In the adult life, MMP-14 is also required for the wound healing process. All of these functions are related to MMP-14's cleavage or activation of the protein within its substrate profile, which includes proteins in ECM, pro-MMPs, cell-adhesion molecules, cytokines, growth factors and receptors on the cell membrane. Recent studies have also demonstrated the activation of signal transduction pathways via the cytoplasmic tail of MMP-14 important for the invasion process. Functions of MMP-14 can be summarized under the categories of activation of proMMMPs; degradation of ECM; shedding of cell surface molecules; cleavage of cytokines and growth factors; and activation of ERK cascade.

I-) Activation of proMMPs and degradation of ECM
Pro-MMP2 was the first identified substrate of MMP-14 and the trimolecular complex consisting of MMP-14 and proMMP2-TIMP2 has been investigated very well for many years. TIMP2 (tissue inhibitor of metalloproteinases-2) is actually the inhibitor of the MMPs. However, low concentrations of TIMP-2 aids in the activation of proMMP-2 by MMP-14 within this complex by binding to the catalytic domain of MMP-14 and the C-terminal domain of pro-MMP2. Following the formation of the triplex, a second MMP-14, which is free of TIMP-2, forms a dimer with the pre-existing MMP-14 on the cell membrane and cleaves the latent pro-MMP2 to produce active MMP2. Active MMP-2 can then participate in other events such as the degradation of collagen type-IV, a major protein component of the basement membrane, which is not cleaved by MMP-14 itself. Another substrate of MMP-14 within the MMP family is the pro-MMP-13, which also functions as a collagenase in the surrounding tissue after its activation.
Besides activation of MMPs, especially pro-MMP-2, MMP-14 cleaves many proteins in the ECM and changes the composition of the matrix. Type I-Type II-Type III collagen, gelatin, fibronectin, laminin-1 and -5, fibrin and proteoglycans are the major direct targets of MMP-14 in the extracellular environment. Out of these substrates, collagen makes up a significant portion of the ECM and acts as a barrier for migratory cells. Within the collagenases, which includes MMP-1, MMP-2, MMP-8, MMP-13, only MMP-14 can stimulate invasion into collagen by epithelial cells, fibroblasts, and cancer cells. MMP-14 concentrates in the protrusions of the cells, called lamellipodia in normal cells and invadopodia in cancer cells, to induce a significant increase in cell migration and invasion by degrading components of the ECM and making a path in through the surrounding tissue. In this aspect, MMP-14 should be bound to the plasma membrane in vivo, as membrane-bound MMP-14 has been demonstrated to be more proteolytically active than the soluble recombinant MMP-14.

II-) Shedding of cell surface molecules
Studies underlying the mechanism of the constitutive shedding of CD44 from the human melanoma cell surface implicated the necessity of MMP-14 with the presence of ADAM-10 for this process. Especially in the hyaluronan based matrix, cleavage of CD44 at the stem region by MMP-14 sheds these molecules from the cell surface and concurrently promotes the migration of the cells from the leading edge. Another cell adhesion molecule, E-cadherin, is also cleaved by MMP-14 to disrupt contact between cells. In the ischemia-induced ARF (acute renal failure), MMP-14 expression is required for the disruption of the cadherin/catenin complex. Syndecan-1 is another cell surface molecule which is cleaved by MMP-14.

III-) Cleavage of cytokines and growth factors
MMP-14 indirectly plays a major role in cleavage of the cytokines and growth factors by activating pro-MMP-2 and pro-MMP13. It also makes direct contact with several chemokines and growth factors including; the neutrophil chemokine IL-8, secretory leukocyte protease inhibitor, pro-tumor necrosis factor, death receptor-6, and connective tissue growth factor.

IV-) Activation of ERK cascade by the cytoplasmic tail of MMP-14
In several studies, overexpression of MMP-14 has been reported to activate the ERK cascade. It is not yet clear how MMP-14 activates ERK signalling, but overexpression of the cytoplasmic-deleted form of MMP-14 has been shown to eradicate ERK activation. Within the cytoplasmic tail, the 573YCQR576 motif has been suggested to be involved in ERK activation. In addition to ERK activation, the role of MMP-14 in the p38 and JNK pathway has also been investigated.

V-) Inhibition of MMP-14 function
Function of MMP-14 can be abolished either by TIMPs (Tissue Inhibitor of MetalloProteinases) or proteolytic degradation. TIMP-2, -3 and -4 but not TIMP-1 specifically inactivates the functions of MMP-14. Besides TIMPs, RECK and N-Tes can also block the activity of MMP-14 in a similar manner. For the proteolytic cleavage of MMP-14, membrane bound MMP-14 should be internalized by the clathrin-dependent and caveolae-dependent pathways. There is an AP-2 binding site in the cytoplasmic domain of MMP-14, 571LLY573 which is required for the incorporation of MMP-14 into clathrin-coated vesicles. The palmitoylation of the C574 right after the AP-2 binding site has also been demonstrated to be an essential modification for the internalization of MMP-14.

Homology All MT-MMPs have shown a 40-50% identity according to their amino acid sequence. In the phylogenetic tree, MMP-14 shares the highest similarity rate with MT2-MMP (MMP-15).

Implicated in

Entity Various cancers
Note Degradation of the ECM by MMP-14 has been linked to proliferation, invasion and metastasis of cancer cells in most cancer types. The expression level of MMP-14 has also been correlated with invasiveness in many cancer cell lines, especially for breast carcinoma. Increase in the MMP-14 expression level has also been observed in a variety of human tumors, including lung, gastric, breast, colon, liver, pancreatic, thyroid, head and neck, ovarian, prostate, bladder, cervical and brain tumors. Genetic alterations, such as gene amplification or activating mutations, have not been observed for MMP-14 in these cancer types, therefore up regulation of MMP-14 has been linked to the transcriptional changes during tumor formation. Immunohistochemical and in-situ hybridization analysis have demonstrated the presence of MMP-14 in both tumor cells and stromal cells. Interestingly, most of the MMP-14 expression is produced by the stromal cells rather than the cancer cells in many tumor types, including breast and lung tumors. The possible explanation for this observation is the production of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) by the cancer cells on their cell surface. EMMPRIN stimulates the surrounding stromal cells to produce MMPs, including MMP-14. However, in some human cancers, including thyroid, brain, and head and neck cancer, a majority of the MMP-14 expression has been shown to be produced by the cancer cells rather than surrounding stromal cells. Another major role of the MMP-14 expression for tumor formation is the upregulation of VEGF production. VEGF is the key molecule for the vascularisation of tumor cells and angiogenesis. For the VEGF gene transcription, C-terminal of MMP-14 in the cytoplasmic tail has a structural region composed of 574CQRSLLDKV582.
  
Entity Atherosclerosis
Note In the numerous stages of atherosclerosis, pro-inflammatory molecules such IL-1a, TNF-a and oxidized-LDL trigger the smooth muscle cells (SMC) and macrophages to increase their levels of MMP-14. Higher expression of MMP-14 activates its downstream molecule, pro-MMP-2, and then both MMP-14 and MMP-2 contribute to the abnormal matrix turnover, leading to the atherosclerotic plaques in the walls of arteries.
  
Entity Rheumatoid disease
Note It has been reported that fibroblasts, macrophages, and osteoclast-like cells in both the lining and sublinig layers of the rheumatoid synovial tissue have higher expression of MMP-14 and MT3-MMP. Effects of MMP-14 have been implicated in the destruction of tissue seen in arthritis. Successful suppression of the joint destruction has also been observed after treatment with one of the MMP-14 inhibitors, called FR217840.
  
Entity Neurologic disease
Note Neurons and astrocytes have been known to express MMPs and remodel the ECM after nerve injury in the body. In the case of amyotrophic lateral sclerosis, MMP-14 expression has been found to be increased in the astrocytes of affected tissues of the mouse central nervous system.
  
Entity Lung disease
Note Vascular endothelial cells and bronchial epithelial cells of the lung were injured by the high volume ventilation in the ventilator-induced lung (VIL) rat model. In the injured cells of the VIL, an increase in the MMP-14 expression has been reported. Prinomastat, an MMP-14 inhibitor, treatment of the VIL rat has also been shown to abolish the injury.
  
Entity Kidney disease
Note Data suggest that the development of crescentic glomerulonephritis, a kidney disease characterized by inflammation of the glomeruli or small blood vessels, triggered by the expression of MMP-14 in macrophages. In this disease, MMP-14 activates proMMP-2, and then they both contribute to the pathological degradation of the ECM.
  

External links

Nomenclature
HGNC (Hugo)MMP14   7160
Cards
AtlasMMP14ID41391ch14q11
Entrez_Gene (NCBI)MMP14  4323  matrix metallopeptidase 14 (membrane-inserted)
GeneCards (Weizmann)MMP14
Ensembl (Hinxton)ENSG00000157227 [Gene_View]  chr14:23305742-23316808 [Contig_View]  MMP14 [Vega]
ICGC DataPortalENSG00000157227
cBioPortalMMP14
AceView (NCBI)MMP14
Genatlas (Paris)MMP14
WikiGenes4323
SOURCE (Princeton)NM_004995
Genomic and cartography
GoldenPath (UCSC)MMP14  -  14q11.2   chr14:23305742-23316808 +  14q11-q12   [Description]    (hg19-Feb_2009)
EnsemblMMP14 - 14q11-q12 [CytoView]
Mapping of homologs : NCBIMMP14 [Mapview]
OMIM600754   
Gene and transcription
Genbank (Entrez)AK291325 AK312657 BC039581 BC064803 BQ009340
RefSeq transcript (Entrez)NM_004995
RefSeq genomic (Entrez)AC_000146 NC_000014 NC_018925 NT_026437 NW_001838110 NW_004929393
Consensus coding sequences : CCDS (NCBI)MMP14
Cluster EST : UnigeneHs.2399 [ NCBI ]
CGAP (NCI)Hs.2399
Alternative Splicing : Fast-db (Paris)GSHG0008718
Alternative Splicing GalleryENSG00000157227
Gene ExpressionMMP14 [ NCBI-GEO ]     MMP14 [ SEEK ]   MMP14 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP50281 (Uniprot)
NextProtP50281  [Medical]
With graphics : InterProP50281
Splice isoforms : SwissVarP50281 (Swissvar)
Catalytic activity : Enzyme3.4.24.80 [ Enzyme-Expasy ]   3.4.24.803.4.24.80 [ IntEnz-EBI ]   3.4.24.80 [ BRENDA ]   3.4.24.80 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)CYSTEINE_SWITCH (PS00546)    HEMOPEXIN (PS00024)    HEMOPEXIN_2 (PS51642)    ZINC_PROTEASE (PS00142)   
Domains : Interpro (EBI)Hemopexin-like_dom [organisation]   Hemopexin-like_repeat [organisation]   Hemopexin_CS [organisation]   MetalloPept_cat_dom [organisation]   MMP14 [organisation]   Pept_M10_metallopeptidase [organisation]   Pept_M10A [organisation]   Pept_M10A_metallopeptidase_C [organisation]   Pept_M10A_stromelysin-type [organisation]   Pept_M10A_Zn_BS [organisation]   Peptidase_Metallo [organisation]   Peptidoglycan-bd-like [organisation]  
Related proteins : CluSTrP50281
Domain families : Pfam (Sanger)DUF3377 (PF11857)    Hemopexin (PF00045)    Peptidase_M10 (PF00413)    PG_binding_1 (PF01471)   
Domain families : Pfam (NCBI)pfam11857    pfam00045    pfam00413    pfam01471   
Domain families : Smart (EMBL)HX (SM00120)  ZnMc (SM00235)  
DMDM Disease mutations4323
Blocks (Seattle)P50281
PDB (SRS)1BQQ    1BUV    3C7X    3MA2   
PDB (PDBSum)1BQQ    1BUV    3C7X    3MA2   
PDB (IMB)1BQQ    1BUV    3C7X    3MA2   
PDB (RSDB)1BQQ    1BUV    3C7X    3MA2   
Human Protein AtlasENSG00000157227 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP50281
HPRD02856
IPIIPI00218398   IPI01022293   IPI01022788   
Protein Interaction databases
DIP (DOE-UCLA)P50281
IntAct (EBI)P50281
FunCoupENSG00000157227
BioGRIDMMP14
InParanoidP50281
Interologous Interaction database P50281
IntegromeDBMMP14
STRING (EMBL)MMP14
Ontologies - Pathways
Ontology : AmiGOossification  angiogenesis  ovarian follicle development  response to hypoxia  endothelial cell proliferation  sequence-specific DNA binding transcription factor activity  metalloendopeptidase activity  integrin binding  calcium ion binding  protein binding  cytoplasm  Golgi lumen  plasma membrane  integral component of plasma membrane  regulation of transcription, DNA-templated  proteolysis  response to oxidative stress  zinc ion binding  male gonad development  response to mechanical stimulus  positive regulation of peptidase activity  peptidase activator activity  extracellular matrix disassembly  extracellular matrix organization  positive regulation of cell growth  lung development  positive regulation of cell migration  collagen catabolic process  extracellular matrix  zymogen activation  melanosome  astrocyte cell migration  response to estrogen  branching morphogenesis of an epithelial tube  tissue remodeling  negative regulation of focal adhesion assembly  
Ontology : EGO-EBIossification  angiogenesis  ovarian follicle development  response to hypoxia  endothelial cell proliferation  sequence-specific DNA binding transcription factor activity  metalloendopeptidase activity  integrin binding  calcium ion binding  protein binding  cytoplasm  Golgi lumen  plasma membrane  integral component of plasma membrane  regulation of transcription, DNA-templated  proteolysis  response to oxidative stress  zinc ion binding  male gonad development  response to mechanical stimulus  positive regulation of peptidase activity  peptidase activator activity  extracellular matrix disassembly  extracellular matrix organization  positive regulation of cell growth  lung development  positive regulation of cell migration  collagen catabolic process  extracellular matrix  zymogen activation  melanosome  astrocyte cell migration  response to estrogen  branching morphogenesis of an epithelial tube  tissue remodeling  negative regulation of focal adhesion assembly  
Pathways : BIOCARTAInhibition of Matrix Metalloproteinases [Genes]   
Pathways : KEGGTNF signaling pathway    GnRH signaling pathway   
Protein Interaction DatabaseMMP14
Wikipedia pathwaysMMP14
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MMP14
snp3D : Map Gene to Disease4323
SNP (GeneSNP Utah)MMP14
SNP : HGBaseMMP14
Genetic variants : HAPMAPMMP14
Exome VariantMMP14
1000_GenomesMMP14 
ICGC programENSG00000157227 
Somatic Mutations in Cancer : COSMICMMP14 
CONAN: Copy Number AnalysisMMP14 
Mutations and Diseases : HGMDMMP14
Mutations and Diseases : intOGenMMP14
Genomic VariantsMMP14  MMP14 [DGVbeta]
dbVarMMP14
ClinVarMMP14
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM600754   
MedgenMMP14
GENETestsMMP14
Disease Genetic AssociationMMP14
Huge Navigator MMP14 [HugePedia]  MMP14 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMMP14
Homology/Alignments : Family Browser (UCSC)MMP14
Phylogenetic Trees/Animal Genes : TreeFamMMP14
Chemical/Protein Interactions : CTD4323
Chemical/Pharm GKB GenePA30872
Clinical trialMMP14
Cancer Resource (Charite)ENSG00000157227
Other databases
Probes
Litterature
PubMed354 Pubmed reference(s) in Entrez
CoreMineMMP14
iHOPMMP14
OncoSearchMMP14

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Contributor(s)

Written10-2010Cem Kuscu, Nikki Evensen, Jian Cao
Division of Cancer Prevention, Stony Brook University, Stony Brook, New York 11794, USA

Citation

This paper should be referenced as such :
Kuscu, C ; Evensen, N ; Cao, J
MMP14 (matrix metallopeptidase 14 (membrane-inserted))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(6):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/MMP14ID41391ch14q11.html

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