MMP14 (matrix metallopeptidase 14 (membrane-inserted))

2010-10-01   Cem Kuscu  , Nikki Evensen  , Jian Cao  

Division of Cancer Prevention, Stony Brook University, Stony Brook, New York 11794, USA

Identity

HGNC
LOCATION
14q11.2
LOCUSID
ALIAS
MMP-14,MMP-X1,MT-MMP,MT-MMP
FUSION GENES

DNA/RNA

Atlas Image

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.

Proteins

Atlas Image
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-14s 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 name
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 name
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 name
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 name
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 name
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 name
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
94902751998MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: possible implications for the role of desmoplastic fibroblasts.Afzal S et al
189719592009ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells.Anderegg U et al
181741742008Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer.Cao J et al
147296742004Distinct roles for the catalytic and hemopexin domains of membrane type 1-matrix metalloproteinase in substrate degradation and cell migration.Cao J et al
156370562005Furin directly cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning proteinase.Cao J et al
192866532009Epigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells.Chernov AV et al
160770812006Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14).Covington MD et al
117263972001Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).Foda HD et al
116863002001Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration.Gilles C et al
116841042001Activation of the extracellular signal-regulated protein kinase (ERK) cascade by membrane-type-1 matrix metalloproteinase (MT1-MMP).Gingras D et al
104288491999Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium.Haas TL et al
108785522000Macrophage-derived MT1-MMP and increased MMP-2 activity are associated with glomerular damage in crescentic glomerulonephritis.Hayashi K et al
105209961999MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.Holmbeck K et al
105674001999Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositol-anchored proteinase.Itoh Y et al
116986552001Regulation of membrane-type matrix metalloproteinase 1 activity by dynamin-mediated endocytosis.Jiang A et al
86632551996Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme.Knäuper V et al
110343162000Membrane-type 6 matrix metalloproteinase (MT6-MMP, MMP-25) is the second glycosyl-phosphatidyl inositol (GPI)-anchored MMP.Kojima S et al
198153352010The activity of a designer tissue inhibitor of metalloproteinases (TIMP)-1 against native membrane type 1 matrix metalloproteinase (MT1-MMP) in a cell-based environment.Lee MH et al
189271212009Characterization of the transcriptional regulation of the human MT1-MMP gene and association of risk reduction for focal-segmental glomerulosclerosis with two functional promoter SNPs.Munkert A et al
166805732006Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer.Overall CM et al
108577812000Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis.Pap T et al
100851371999Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP.Pei D et al
155925042005Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma.Petrella BL et al
196925882009Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia.Poincloux R et al
102070131999Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase.Rajavashisth TB et al
110079692000Elevated expression of membrane type 1 metalloproteinase (MT1-MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system.Rathke-Hartlieb S et al
194340872009Shedding light on proteolytic cleavage of CD44: the responsible sheddase and functional significance of shedding.Stamenkovic I et al
75836371995Structural features of a superfamily of zinc-endopeptidases: the metzincins.Stöcker W et al
78906451995Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease.Strongin AY et al
151180972004Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates.Tam EM et al
108401632000Granulocyte-macrophage colony-stimulating factor upregulates matrix metalloproteinase-2 (MMP-2) and membrane type-1 MMP (MT1-MMP) in human head and neck cancer cells.Tomita T et al
107060982000Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors.Velasco G et al
76491591995cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment.Will H et al
120938182002Transcription factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix metalloproteinase expression in endothelium.Yun S et al
107377632000Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.Zhou Z et al
94952491998Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation.Zucker S et al

Other Information

Locus ID:

NCBI: 4323
MIM: 600754
HGNC: 7160
Ensembl: ENSG00000157227

Variants:

dbSNP: 4323
ClinVar: 4323
TCGA: ENSG00000157227
COSMIC: MMP14

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000157227ENST00000311852P50281
ENSG00000157227ENST00000547279F8VP90
ENSG00000157227ENST00000548761F8W1B7

Expression (GTEx)

0
100
200
300
400
500
600
700

Pathways

PathwaySourceExternal ID
GnRH signaling pathwayKEGGko04912
GnRH signaling pathwayKEGGhsa04912
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Extracellular matrix organizationREACTOMER-HSA-1474244
Degradation of the extracellular matrixREACTOMER-HSA-1474228
Activation of Matrix MetalloproteinasesREACTOMER-HSA-1592389
Collagen degradationREACTOMER-HSA-1442490

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
386610402024MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells.0
386702102024Exosomal lncRNA-MIAT promotes neovascularization via the miR-133a-3p/MMP-X1 axis in diabetic retinopathy.0
387668532024Calreticulin regulates the expression of MMP14 and ADAR1 through EIF2AK2 signaling to promote the proliferation and progression of malignant melanoma cells.0
386610402024MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells.0
386702102024Exosomal lncRNA-MIAT promotes neovascularization via the miR-133a-3p/MMP-X1 axis in diabetic retinopathy.0
387668532024Calreticulin regulates the expression of MMP14 and ADAR1 through EIF2AK2 signaling to promote the proliferation and progression of malignant melanoma cells.0
359440802023MT1-MMP and ADAM10/17 exhibit a remarkable overlap of shedding properties.5
367652962023MMP14 expression levels accurately predict the presence of extranodal extensions in oral squamous cell carcinoma: a retrospective cohort study.2
368838772023Tumour Suppressor Neuron Navigator 3 and Matrix Metalloproteinase 14 are Co-expressed in Most Melanomas but Downregulated in Thick Tumours.0
370864942023ALIX promotes cell migration and invasion of head and neck squamous cell carcinoma by regulating the expression of MMP9, MMP14, VEGF-C.4
371050822023Characterizing the function-related specific assembly pattern of matrix metalloproteinase-14 by dSTORM imaging.1
371623372023Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites.1
371690792023Degradomic Identification of Membrane Type 1-Matrix Metalloproteinase as an ADAMTS9 and ADAMTS20 Substrate.1
376965802023KIF16B drives MT1-MMP recycling in macrophages and promotes co-invasion of cancer cells.1
379044292023Expression of MMP-14 and its role in bone destruction in middle ear cholesteatoma: A prospective observational study.0

Citation

Cem Kuscu ; Nikki Evensen ; Jian Cao

MMP14 (matrix metallopeptidase 14 (membrane-inserted))

Atlas Genet Cytogenet Oncol Haematol. 2010-10-01

Online version: http://atlasgeneticsoncology.org/gene/41391/js/favicon/favicon-32x32.png