Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation of the angiogenic process requires a locally confined and time-limited proteolysis of the basement membrane (BM) components at the site of new vessel sprout. Gelatinase A, a member of the matrix metalloproteinase family, degrades BM type IV collagen and is involved in the BM breakdown by migrating tumor cells and endothelial cells (EC). Gelatinase A is synthesized as latent proenzyme and must be activated in order to express its proteolytic activity. A plasma membrane-dependent mechanism of activation has been described for several tumor and transformed cells lines. In the present study, we show that latent (72 kD) and mature (62-59 kD) forms of gelatinase A are present in EC membrane fraction from Triton X-114 extract while only latent form is found in the cytosolic fraction. The incubation of EC membrane fraction with exogenous latent gelatinase A resulted in a significant activation giving rise to 62-59 kD mature forms. 12-O-tetradecanoylphorbol-13-acetate (TPA), a strong potentiator of angiogenesis in vitro and in vivo, increases the amount of both latent and activated forms of gelatinase A in EC membrane fraction as well as the ability of this latter fraction to activate exogenous latent gelatinase A. We show that the mRNA transcript coding for the membrane-integrated MMP, the MT-MMP, previously described as a potential gelatinase A activator in invasive tumor cells is also expressed in vascular EC and is regulated through a TPA sensitive process. This enzyme may be responsible for membrane-dependent gelatinase A activation in normal vascular EC and may therefore be a determinant in the control of BM proteolysis during angiogenesis.
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PMID:Plasma membrane-dependent activation of gelatinase A in human vascular endothelial cells. 759 26

The effect of chronological aging and photoaging (UV-radiation) on elastase-type enzyme activity of hairless mouse skin was studied. Aging resulted in the increase of elastase type endopeptidase activity extractable from mouse skins. Both chronic UVA and UVB radiation resulted in a significant increase of elastase type activity. PBS extracted only small part of the elastase activity, UV-A produced an increase of about 90-120% according to the type of irradiation (xenon or UV-A SUN) and UV-B produced a 72% increase. Extraction by Triton X-100 suggested that most of the activity is bound to cells and fibrous structures. EDTA inhibited 80-90% of the elastase activity in chronologically aged skin extracts and also the activity induced by UVA radiation suggesting that metallo-elastase(s) are involved. About 30% of the UVB induced activity could only be inhibited by EDTA and about 50% by PMSF suggesting that irradiation by UVB increased more serine endopeptidase activity but also MMP-activity. Chronic UVA radiation produced an increase of skin elastase activity equivalent to that observed after 24 months of aging in non-irradiated animals (approximately 100 weeks) corresponding to approximately 90% of total life span of these mice. The total increase produced by UVB was less, but the strong increase of a serine elastase, presumably from PMN-s, appear to produce a much more pronounced biological activity as shown by the presence of fibronectin degradation products in skin extracts. Such degradation products were shown to exert harmful effects on tissues. These results may well have biological significance and distinguish chronological aging and photoaging.
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PMID:Age dependent increase of elastase type protease activity in mouse skin. Effect of UV-irradiation. 1115 76

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-associated MMP that has been recently reported to have a central role in tumour cell invasion. Here we report that both the native and overexpressed recombinant forms of MT1-MMP are highly enriched in low-density Triton X-100-insoluble membrane domains that contain the caveolar marker protein caveolin 1. Moreover, the MT1-MMP-dependent activation of proMMP-2 induced by concanavalin A and cytochalasin D was correlated with the processing of MT1-MMP to its proteolytically inactive 43 kDa fragment in U-87 glioblastoma and HT-1080 fibrosarcoma tumour cell lines; this processing was also preferentially observed within the caveolar fraction. Interestingly, whereas the expression of caveolin 1 had no effect on the MT1-MMP-dependent activation of proMMP-2, its co-expression with MT1-MMP antagonized the MT1-MMP-increased migratory potential of COS-7 cells. Taken together, our results provide evidence that MT1-MMP is preferentially compartmentalized and proteolytically processed in caveolae of cancer cells. The inhibition of MT1-MMP-dependent cell migration by caveolin 1 also suggests that the localization of MT1-MMP to caveolin-enriched domains might have an important function in the control of its enzymic activity.
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PMID:Localization of membrane-type 1 matrix metalloproteinase in caveolae membrane domains. 1117 Oct 51

Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.
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PMID:Hyaluronan cell surface binding is induced by type I collagen and regulated by caveolae in glioma cells. 1501 31

Complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1 (CDCP1) is a transmembrane protein that regulates anchorage-independent growth and cancer cell migration and invasion. Expression of CDCP1 is detected in a number of cancer cell lines and tissues and is closely correlated with poor prognosis. Invadopodia are actin-based protrusions on the surface of invasive cancer cells that promote the degradation of the extracellular matrix (ECM) via localized proteolysis, which is mainly mediated by membrane type 1 matrix metalloproteinase (MT1-MMP). MT1-MMP is accumulated at invadopodia by targeted delivery via membrane trafficking. The present study shows that CDCP1 is required for ECM degradation by invadopodia in human breast cancer and melanoma cells. CDCP1 localized to caveolin-1-containing vesicular structures and lipid rafts and was detected in close proximity to invadopodia. Further biochemical analysis revealed that substantial amounts of CDCP1 existed in the Triton X-100 insoluble lipid raft fraction. CDCP1 was coimmunoprecipitated with MT1-MMP and colocalized with MT1-MMP at the vesicular structures. The siRNA-mediated knockdown of the CDCP1 expression markedly inhibited MT1-MMP-dependent ECM degradation and Matrigel invasion and reduced the accumulation of MT1-MMP at invadopodia, as shown by immunofluorescence analysis. These results indicate that CDCP1 is an essential regulator of the trafficking and function of MT1-MMP- and invadopodia-mediated invasion of cancer cells.
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PMID:CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. 2343 92

Matrix metalloproteinase-27 (MMP-27) is poorly characterized. Sequence comparison suggests that a C-terminal extension (CTE) includes a potential transmembrane domain as in some membrane-type (MT)-MMPs. Having noticed that MMP-27 was barely secreted, we investigated its subcellular localization and addressed CTE contribution for MMP-27 retention. Intracellular MMP-27 was sensitive to endoglycosidase H. Subcellular fractionation and confocal microscopy evidenced retention of endogenous MMP-27 or recombinant rMMP-27 in the endoplasmic reticulum (ER) with locked exit across the intermediate compartment (ERGIC). Conversely, truncated rMMP-27 without CTE accessed downstream secretory compartments (ERGIC and Golgi) and was constitutively secreted. CTE addition to rMMP-10 (a secreted MMP) caused ER retention and blocked secretion. Addition of a PKA target sequence to the cytosolic C-terminus of transmembrane MT1-MMP/MMP-14 led to effective phosphorylation upon forskolin stimulation, but not for MMP-27, excluding transmembrane anchorage. Moreover, MMP-27 was protected from digestion by proteinase K. Finally, MT1-MMP/MMP-14 but neither endogenous nor recombinant MMP-27 partitioned in the detergent phase after Triton X-114 extraction, indicating that MMP-27 is not an integral membrane protein. In conclusion, MMP-27 is efficiently retained within the ER due to its unique CTE, which does not lead to stable membrane insertion. This could represent a novel ER retention system.
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PMID:A unique C-terminal domain allows retention of matrix metalloproteinase-27 in the endoplasmic reticulum. 2454 19