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evolution
membrane-type matrix metalloproteinase 1 (MT1-MMP, also MMP14) is a type I membrane protein belonging to the MT-MMP family
malfunction
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increased levels of soluble MT1-1/MMP-14 in the serum of breast cancer patients may have implications in the pathogenesis of the disease
malfunction
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loss of MMP14 activity increases steady-state vascular leakage, MMP14 activity impacts vascular leakage, mechanism, overview
malfunction
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loss of MMP14 activity increases steady-state vascular leakage, MMP14 activity impacts vascular leakage, mechanism, overview
malfunction
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MMP14 mediates tumor cell surface MHC class I chain-related molecule A shedding, suppression of MMP14 expression blocks MICA shedding, while overexpression of MMP14 enhances it. The regulation is independent of the activity of a disintegrin and metalloproteinases, overview
malfunction
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MMP14 mediates tumor cell surface MHC class I chain-related molecule A shedding, suppression of MMP14 expression blocks MICA shedding, while overexpression of MMP14 enhances it. The regulation is independent of the activity of a disintegrin and metalloproteinases, overview
malfunction
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membrane-type 1 matrix metalloproteinase knockdown in DU-145 cells decreases activity of reactive oxygen species 8-hydroxydeoxyguanosine
malfunction
MT1-MMP inhibition restores sensory axon regeneration and attenuates hypersensitivity caused by peripheral nerve injury
malfunction
a single mutation in the putative membrane interaction region of MT1-MMP (Ser466Pro) results in lower enzyme activation by bicelles
malfunction
Cartoon mice harbor the single point mutation S466P in the MT1-MMP hemopexin domain, a 200-amino acid segment. The S466P substitution generates a misfolded, temperature-sensitive mutant that is abnormally retained in the endoplasmic reticulum (ER). The MT1-MMPS466P mutation replicates the phenotypic status of Mt1-mmp-null animals as well as the functional characteristics of MT1-MMP-/- cells. The wild-type hemopexin domain does not play a required role in regulating MT1-MMP trafficking, as a hemopexin domain-deletion mutant is successfully mobilized to the cell surface and displays nearly normal collagenolytic activity. Cartoon mice exhibit a pattern of stunted growth, kyphosis, and rounded skulls, Cartoon mouse phenotype, detailed overview. Cartoon mouse fibroblasts are devoid of pericellular collagenolytic activity
malfunction
deletion of the MT1-MMP cytoplasmic tail enhances cell surface activity, with both kcat and KM values affected, while deletion of the hemopexin-like domain negatively impacts KM and increases kcat
malfunction
functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome (WS) phenotype. The WS phenotype includes craniofacial malformations, kyphosis, short-stature, and reduced bone density owing to defective collagen remodeling
malfunction
membranous ossifying Weberian vertebral bodies in mmp14a/b KO fish are irregularly shaped, with clusters of multinucleated cells in their dorsal aspect. Mutant mmp14a/b KO fish have abnormal endochondral and membranous ossification, but collagen deposition is unaffected by mmp14a/b KO
malfunction
Mmp14-/- mice display defects in branching activity, phenotype, overview. Immunohistological assessments of Mmp14-/- mammary gland sections reveal no differences in the expression or organization of CK18, CK14, or alphaSMA from P0 through P10. MMP14 can activate MMP2 in vivo, a proteinase thought to mediate MMP14 function and to compensate partially for Mmp14 deficiency
metabolism
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MMP-14 is involved in gene network of deregulated genes associated to cell cycle, overview
metabolism
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MMP-14 is involved in the extracellular matrix metabolism
metabolism
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type I collagen fibrils posttranslationally regulate perivascular MMP activity and TGFbeta bioavailability, which in turn regulate vascular homeostasis by altering vessel stability and leakage. Matrix metalloproteinase 14 and transforming growth factor beta 1 are involved in a pathway regulating vessel stability in tissues, the pathway mediates vessel stability and vascular response to tissue injury
metabolism
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type I collagen fibrils posttranslationally regulate perivascular MMP activity and TGFbeta bioavailability, which in turn regulate vascular homeostasis by altering vessel stability and leakage. Matrix metalloproteinase 14 and transforming growth factor beta 1 are involved in a pathway regulating vessel stability in tissues, the pathway mediates vessel stability and vascular response to tissue injury
metabolism
an MT1-MMP/Notch1 signaling pathway supports melanoma cell growth
metabolism
cleavage of hepatocyte growth factor activator inhibitor-1 by membrane-type MMP-1 activates matriptase
metabolism
branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases MMP14 (MT1-MMP) and MMP15 (MT2-MMP), which drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. Different roles played by MMP14 or MMP15 in the mammary gland epithelial compartment and in development of mammary gland, overview. Whereas MMP14 promotes white fat-associated adipogenesis in the developing mammary gland, MMP15 serves as an endogenous suppressor of beige/brown fat production
metabolism
CCN5 (WISP2) is processed in the variable region by MMP14 and MMP2, as well as by MMP1, 3, 7, 8, 9 and 15. CCN5 cleavage by proangiogenic MMPs results in removal of an angiogenic brake held by CCN5. CCN3 is processed most efficiently by MMP14, 2 and 1 from about 30 kDa to fragments of 20-25 kDa, and less efficiently by MMP8 and 9
metabolism
matrix metalloproteinases (MMP) are an important family of proteases which catalyze the degradation of extracellular matrix components
metabolism
MMP14 and MMP15 are involved in trophoblast invasion
physiological function
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an essential role for MT1-MMP in the process of angiogenesis and bone growth. Tetraspanins are attracting attention as binding proteins of MT1-MMP, which regulate subcellular localization and compartmentalization of MT1-MMP and consequent MT1-MMP activities. MT1-MMP plays an essential role in angiogenesis, CD151 may contribute to endothelial homeostasis through the regulation of MT1-MMP. CD9, CD81, and TSPAN12 also associate with cell surface molecules including integrins. Tetraspanin-regulated cell surface localization of MT1-MMP increases the local concentration for focal proteolysis within the pericellular environment and leads to efficient extracellular matrix degradation and MMP-2 activation
physiological function
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membrane-type 1 matrix metalloproteinase 1 is a potent modulator of the pericellular microenvironment and regulates cellular functions in physiological and pathological settings in mammals. MT1-MMP mediates its biological effects through cleavage of specific substrate proteins. Cleavage of collagen by MT1-MMP regulates cell growth and invasion in a collagen-rich environment
physiological function
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MMP14 regulates TGFbeta bioactivity and vascular stability, MMP14 also regulates the bioavailability of several chemokines and growth factors. MMP14-mediated resistance to vascular and VEGF leakage is accompanied by decreased appearance of leakage sites in vessels with perivascular cell coverage
physiological function
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podosomes mediate migration of dendritic cells through tissues by means of myosin-II-dependent protrusion coupled to MMP-14-dependent degradation and endocytosis. Degradation, protrusion and endocytosis in this system are dependent on the matrix metalloproteinase MMP-14
physiological function
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tetraspanins are attracting attention as binding proteins of MT1-MMP, which regulate subcellular localization and compartmentalization of MT1-MMP and consequent MT1-MMP activities. MT1-MMP plays an essential role in angiogenesis, CD151 may contribute to endothelial homeostasis through the regulation of MT1-MMP. CD9, CD81, and TSPAN12 also associate with cell surface molecules including integrins. Tetraspanin-regulated cell surface localization of MT1-MMP increases the local concentration for focal proteolysis within the pericellular environment and leads to efficient extracellular matrix degradation and MMP-2 activation
physiological function
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MT-MMP1 must form a homophilic ternary complex with TIMP-2 and pro-MMP-2 to activate MMP-2
physiological function
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in endothelial cells, MMP-14 is the main endoglin shedding protease
physiological function
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MT1-MMP coexpressed with heparin-binding epidermal growth factor in ovarian carcinoma cells potentiates the activity of heparin-binding epidermal growth factor to promote invasive tumor growth and spreading in vivo. MT1-MMP promotes heparin-binding epidermal growth factor-dependent proliferation of ovarian carcinoma cells
physiological function
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oxidative stress and prostate cancer progression are elicited by membrane-type 1 matrix metalloproteinase
physiological function
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the processing of heparin-binding epidermal growth factor by MT1-MMP converts the substrate into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo
physiological function
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the processing of heparin-binding epidermal growth factor by MT1-MMP converts the substrate into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo
physiological function
activated hepatic stellate cells require membrane type 1 matrix metalloproteinase-cleaved collagen for their survival
physiological function
both neuronal glial antigen 2 shedding and axonal growth depend on the pericellular remodeling executed by MT1-MMP/MMP-14
physiological function
in tumor cells the enzyme downregulates fibroblast growth factor-2 signaling by reducing the amount of fibroblast growth factor-2 signaling bound to the cell surface with high and low affinity
physiological function
membrane type 1 matrix metalloproteinase-dependent activation of MMP-2 is required for optimal neurite outgrowth
physiological function
overexpression of MT1-MMP induces epithelial-to-mesenchymal transition and results in the acquisition of cancer stem cell-like properties in SCC-9 cells. Upon up-regulation of the enzyme, the cells undergo EMT, in which they presented a fibroblast-like phenotype and have a decreased expression of epithelial markers (E-cadherin, cytokeratin18 and beta-catenin) and an increased expression of mesenchymal markers (vimentin and fibronectin)
physiological function
the enzyme is critical to monocyte migration
physiological function
the enzyme promotes cancer cell invasion. The MT-LOOP-dependent enzyme localization to the cell adhesion complex promotes cellular invasion (the MT-LOOP is a region in the catalytic domain of MT1-MMP (163PYAYIREG170))
physiological function
the enzyme promotes Notch1 activation in melanoma cells
physiological function
the enzyme promotes tumor progression by circumventing the collagen-induced up-regulation of the pro-apoptotic tumor suppressor BIK. The enzyme contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells
physiological function
cell surface localization of MT1-MMP restricts substrate binding and protein-coupled motions (based on changes in both kcat and KM) for catalysis
physiological function
collagen degradation and proMMP-2 activation are major functions of MT1-MMP to promote cancer cell invasion. Both processes require MT1-MMP homodimerization on the cell surface
physiological function
enzyme MT1-MMP plays a crucial role in many physiological and pathological processes, especially in tumor invasion and metastasis
physiological function
heterotrimeric G proteins directly regulate membrane-localized MMP14/MT1-MMP, resulting in HB-EGF release and EGF receptor transactivation. Analysis of the membrane-delimited mechanism for EGF receptor transactivation. MMP14 is a heterotrimeric G protein-regulated effector
physiological function
heterotrimeric G proteins directly regulate membrane-localized MMP14/MT1-MMP, resulting in HB-EGF release and EGF receptor transactivation. Analysis of the membrane-delimited mechanism for EGFreceptor transactivation. MMP14 is a heterotrimeric G protein-regulated effector
physiological function
membrane type 1 matrix metalloproteinase (MT1-MMP) is a type I transmembrane cell-surface protease that has been implicated in numerous pathologies. The pericellular collagenase membrane-type 1 matrix metalloproteinase (MT1-MMP) and membrane-mimicking environments interplay in substrate binding and processing. MT1-MMP transiently associates with bicelles and cells through distinct residues in blades III and IV of its hemopexin-like domain, while binding of collagen-like triple helices occurs within blades I and II of this domain. MT1-MMP collagenolytic activity appears critical for transmigration of tumor cells, endothelial cells, and fibroblasts through collagen matrices, while post-myocardial infarction survival has been correlated to the collagenolytic potential of cardiac fibroblasts, where MT1-MMP is the dominant collagenase within myocardial tissues
physiological function
membrane type 1-matrix metalloproteinase (MT1-MMP or MMP-14) is involved in the degradation of extracellular matrix and tumor invasion. MT1-MMP is involved in the mediation of pericellular proteolysis of extracellular matrix components, essential for the physiological remodeling processes such as tissue repair, development, and morphogenesis. MT1-MMP is overexpressed in many cancer types and increases tumor cell growth, invasion, and metastasis by degrading extracellular matrix components and making paths through surrounding tissues
physiological function
membrane type-1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in cellular growth and migration by activating proMMP-2 into active MMP2. MT1-MMP inhibits the tetherin activity of Bst-2 (bone marrow stromal cell antigen 2), a type II membrane protein, by interacting with Bst-2, not via downregulation of Bst-2. The cytoplasmic domains of both Bst-2 and MT1-MMP play critical roles within this interaction. Bst-2 inhibits MT1-MMP activity through their interaction resulting in a decrease of proMMP2 activation
physiological function
membrane type-1 MMP (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of MMP-2 and the release of matrix bound TGF-beta. Enzyme MT1-MMP is subject to protein kinase C (PKC)-mediated regulation via reversible phosphorylation, which alters intracellular trafficking and activity with TAA. MT1-MMP abundance increases in aortas from both TAA groups. Active MMP-2 is increased only in large TAAs. Abundance of phosphorylated MT1-MMP and activated-PKC-delta is enhanced in small versus large TAAs. Phosphorylation of MT1-MMP mediates its activity through directing cellular localization, shifting its role from MMP-2 activation to intracellular signaling
physiological function
metalloproteinase MMP14 (MT1-MMP) drives epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. It plays a role in mammary gland development. Transcriptome profiling reveals a key role for MMP14 and MMP15 in regulating mammary gland adipocyte differentiation. MMP14 promotes the generation of white fat depots crucial for energy storage. MMP14-dependent regulation of branching morphogenesis, overview. MMP14 can activate MMP2 in vivo, a proteinase thought to mediate MMP14 function and to compensate partially for Mmp14 deficiency. Early mammary gland branching proceeds independently of MMP14, MMP14-independent epithelial cell sorting, proliferation, senescence and extracellular matrix organization, overview
physiological function
MMP14 is a regulator of angiogenesis, it cleaves CCN5 and abrogates the angiostatic activity. CCN5 is an angiogenesis inhibitor that is inactivated by MMP14 cleavage. Proteolytic processing of CCN3 by MMP14
physiological function
the cell-surface collagen degradation by MT1-MMP involves DDR2-mediated collagen signaling
physiological function
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heterotrimeric G proteins directly regulate membrane-localized MMP14/MT1-MMP, resulting in HB-EGF release and EGF receptor transactivation. Analysis of the membrane-delimited mechanism for EGF receptor transactivation. MMP14 is a heterotrimeric G protein-regulated effector
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additional information
a small conformational change is detected at 37°C, which is responsible for the change in activity observed at the same temperature. Pressure decreases the enzymatic activity until complete inactivation occurs at 2 kbar. The inactivation is associated with changes in the rate-limiting step of the reaction caused by additional hydration of the active site upon compression and/or minor conformational changes in the active site region
additional information
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a small conformational change is detected at 37°C, which is responsible for the change in activity observed at the same temperature. Pressure decreases the enzymatic activity until complete inactivation occurs at 2 kbar. The inactivation is associated with changes in the rate-limiting step of the reaction caused by additional hydration of the active site upon compression and/or minor conformational changes in the active site region
additional information
an initial structural framework defines the role(s) of cell membranes in modulating proteolysis. Examination of simultaneous membrane interaction and triple-helix binding reveals a possible regulation of proteolysis due to steric effects of the membrane. Activity analysis of MT1-MMP in membrane-like environments, Interaction of the isolated 15N MT1-MMP HPX domain with bilayers, with a collagen-like triple helical peptide (THP) alone or in the presence of bicelles, or with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), interaction of 15N sMT1-MMP with bicelles, NMR spectroscopic analysis, modelling, overview
additional information
DDRs are receptor tyrosine kinases (RTKs) in which phosphorylation of their cytoplasmic domain is induced by binding to collagen at their ectodomain. Discoidin domain receptor 2 (DDR2) mediates type I collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts. Knocking down DDR2, but not the beta1 integrin subunit, a common subunit for all collagen-binding integrins, inhibits the collagen-induced MT1-MMP-dependent activation of pro-MMP-2 and upregulation of MT1-MMP at the gene and protein levels. This DDR2-mediated mechanism is only present in non-transformed mesenchymal cells, as collagen-induced MT1-MMP activation in HT-1080 fibrosarcoma cells and MT1-MMP function in MDA-MB231 breast cancer cells are not affected by DDR kinase inhibition
additional information
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DDRs are receptor tyrosine kinases (RTKs) in which phosphorylation of their cytoplasmic domain is induced by binding to collagen at their ectodomain. Discoidin domain receptor 2 (DDR2) mediates type I collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts. Knocking down DDR2, but not the beta1 integrin subunit, a common subunit for all collagen-binding integrins, inhibits the collagen-induced MT1-MMP-dependent activation of pro-MMP-2 and upregulation of MT1-MMP at the gene and protein levels. This DDR2-mediated mechanism is only present in non-transformed mesenchymal cells, as collagen-induced MT1-MMP activation in HT-1080 fibrosarcoma cells and MT1-MMP function in MDA-MB231 breast cancer cells are not affected by DDR kinase inhibition
additional information
solvent water interactions within the active site of the membrane type I matrix metalloproteinase, crystal structure analysis, quantum mechanics/molecular mechanics geometries and modelling, structure modelling, overview
additional information
the catalytic domain comprises residues Tyr112-Gly284
additional information
visualization of membrane-bound, active MT1-MMP is achieved by fluorescence resonance energy transfer (FRET) imaging of surface-anchored sensors. An initial MT1-MMP sensor was created using the Cys-Pro-Lys-Glu-Ser-Cys-Asn-Leu-Phe-Val-Leu-Lys-Asp sequence, derived from the MT1-MMP cleavage site in proMMP-2. The C-terminus plays a required role in regulating proteolytic activity at the cell surface