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)

Two invasive breast cancer cell lines (MDA-MB-231 and BT-549) were found to be more adherent and have greater migratory capacity on bone marrow fibroblasts than three non-invasive cell lines (MCF-7, T47D and BT-483). Antibodies to the adhesion molecules CD44, E-cadherin, ICAM- 1, and integrin chains alpha2, alpha3, alpha4, alpha5, alpha6, alpha v, beta1, beta3 and beta7 failed to inhibit breast cancer cell migration through bone marrow fibroblasts. Inhibitors of matrix metalloproteases, 1, 10-phenanthroline, Ro-9790, TIMP-1 and TIMP-2 were able to attenuate the migration of MDA-MB-231 cells through bone marrow fibroblast monolayers suggesting a role for these enzymes in the migration of breast cancer cells through bone marrow adherent layers. Co-culture of MDA-MB-231 cells and bone marrow fibroblasts resulted in augmentation of the levels of the matrix metalloproteases MMP-1 and MMP-2 in culture supernatants. Soluble factors produced by bone marrow fibroblasts were responsible for the increase in MMP-1 levels. However, maximal MMP-2 production was dependent on direct contract between the breast cancer cells and the bone marrow fibroblasts. Modulation of MMP production by cell-cell contact or soluble factors suggests a mechanism by which breast cancer cells can enhance their ability to invade the bone marrow microenvironment.
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PMID:Induction of matrix metalloproteinases MMP-1 and MMP-2 by co-culture of breast cancer cells and bone marrow fibroblasts. 1109 87

Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP-processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP-dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.
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PMID:Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. 1138 Oct 77

CD44 is a facultative proteoglycan implicated in cell adhesion and trafficking, as well as in tumor survival and progression. We demonstrate here that CD44 heparan sulfate proteoglycan (CD44HSPG) recruits proteolytically active matrix metalloproteinase 7 (matrilysin, MMP-7) and heparin-binding epidermal growth factor precursor (pro-HB-EGF) to form a complex on the surface of tumor cell lines, postpartum uterine and lactating mammary gland epithelium, and uterine smooth muscle. The HB-EGF precursor within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to, among other events, cell survival. In CD44(-/-) mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired. In both uterine and mammary epithelia of these mice, MMP-7 localization is altered and pro-HB-EGF processing as well as ErbB4 activation are decreased. Our observations provide a mechanism for the assembly and function of a cell surface complex composed of CD44HSPG, MMP 7, HB-EGF, and ErbB4 that may play an important role in the regulation of physiological tissue remodeling.
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PMID:CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. 1182 73

Hybridization with cDNA arrays was used to obtain expression profiles of 263 protein-tyrosine kinase (PTK), protein-tyrosine phosphatase (PTP), dual-specific phosphatase (DuSP), and other genes for the normal prostate tissue, primary prostate carcinomas (PC) of 84 patients, 7 xenografts, and 5 carcinoma cell lines. Analysis of 96 profiles revealed eight clusters of genes coexpressed in PC (coefficient of correlation r > 0.7). According to the known functions of their genes, the clusters were designated as proliferating-cell (CDC42, TOP2A, FGFR3, MYC, etc.), neoangiogenesis and blood-cell (LCK, VAV1, KDR, VEGF, MMP9, SYK, PTPRS, and FLT4), invasion-1 and invasion-2 (ADAM17, TRPM2, DUSP6, VIM, CAV1, CAV2, JAK1, PTPNS1, FYN, and PDGFB), HER2, and PSA/PSM/HER3. Basing on expression profiles of 66 genes, a molecular classification of PC was constructed and allowed discrimination between PC and cell lines or xenografts at 98.9% probability. The results suggested that, along with PSA, PSM (FOLH1), kallikrein-2, and a-2-macroglobulin, cell signaling genes EGFR, HER2, HER3, TOP2, KRT8, KRT18, VEGF, CD44, VIM, CAV1, and CAV2 may serve as diagnostic and prognostic markers in PC. The HER2, VEGF, and CD44 genes and the MMP and ADAM families were assumed to be promising targets for inhibitors of PC cell proliferation and metastasis.
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PMID:[Gene expression profiles of protein kinases and phosphatases obtained by hybridization with cDNA arrays: molecular portrait of human prostate carcinoma]. 1262 52

Much progress has been made in recent years in the understanding of angiogenesis, yet signalling pathways involved remain poorly defined. Here we report that small RhoA GTPase is implicated in the invasion of human microvascular endothelial cells (HMEC-1). Ectopic expression of active-RhoA GTPase induced the expression of MMP-9 metalloproteinase, a key proteinase of the basement membrane, and promoted migration of endothelial cells through a 3D-matrix protein gel. MMP-9 was either directed as vesicular-like patches to the apical side of cells, or addressed to specific membrane sites at the cell surface. Confocal microscopy analyses indeed revealed clustering of MMP-9 in advancing lamellipodia at the forefront of endothelial cells, where this proteinase colocalized with RhoA and CD44, a transmembrane receptor known to be proteolysed in tumor cell progression. In addition, TIMP-1, a natural MMP inhibitor, significantly reduced the invasion of RhoAV14 expressing cells, suggesting that MMP-9 was a critical metalloproteinase responsible, at least partly, for the RhoAV14-induced endothelial cell invasion. We propose that RhoA triggers signalling pathways that, upregulating expression of a proteinase at specific membrane localizations, may confer an highly invasive phenotype to endothelial cells.
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PMID:RhoA induces MMP-9 expression at CD44 lamellipodial focal complexes and promotes HMEC-1 cell invasion. 1464 58

CD44 is a receptor for hyaluronan and mediates signaling that regulates complex cell behavior including cancer cell migration and invasion. Shedding of the extracellular portion of CD44 is the last step in the regulation of the molecule-releasing interaction between the ligand and cell. However, highly glycosylated forms of CD44 have hampered the identification of the exact cleavage sites for shedding and the responsible proteases. In this study, we found that expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) increased shedding of the 65-70 kDa CD44H (standard form) fragments and generated two additional smaller fragments. We purified the shed fragments and identified the cleaved sites by mass spectrometry. Specific antibodies that recognize the newly exposed COOH terminus by cleavage were prepared and used to analyze shedding at each site. Shedding of the 65-70 kDa fragments was inhibited by tissue inhibitor of metalloproteinase 3 (TIMP-3) but not by TIMP-1 and TIMP-2, suggesting involvement of a disintegrin and metalloproteinase (ADAM)-like proteases, although shedding is affected by MT1-MMP. Conversely, shedding of the two smaller fragments was inhibited by TIMP-2 and TIMP-3 but not TIMP-1, suggesting involvement of MT1-MMP itself. Shed fragments cleaved at these sites were also detected in human tumor tissues. Increased shedding at one of the MT1-MMP-sensitive sites was observed in the tumor compared with the surrounding normal tissue. However, no significant difference was observed with shedding by ADAM-like proteases. Thus, the cleavage sites for the shedding of CD44H were identified for the first time, and the results provide a basis for exploring the unknown biologic roles of shedding at different sites.
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PMID:Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase. 1487 15

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

The activity of membrane-type 1 matrix metalloproteinase (MT1-MMP) is a double-edged sword--it is crucial for both physiological processes and disease progression. MT1-MMP modifies various cellular functions and it is, sthus, regulated precisely as a proteinase and as a membrane protein. Recent studies have further revealed that the function of MT1-MMP is modified and regulated by O-glycosylation, interaction with CD44, internalization and recycling. Such multidimensional mechanisms enable MT1-MMP to be regulated spatially and temporally, and are essential for its proper functioning on the cell surface.
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PMID:MT1-MMP: an enzyme with multidimensional regulation. 1527 80

Expression and activity of matrix metalloproteinase-9 (MMP-9) as well as its relationship with hyaluronan (HA) and NF-kappaB activity were analyzed in two murine lymphoma cell lines with dissimilar migration and invasive behavior. MMP activity was evaluated by zymograms in supernatants, membrane extracts of tumor cells, and in the organs invaded by these cells. The more aggressive LBLa cell line showed MMP-9 activity in vitro, which increased after HA treatment and was blocked by anti-CD44 mAb. Such activity was not found in the less aggressive LBLc. MMP-9 and MMP-2 activity was found in organs invaded by both cell lines, although differential MMP-9 activity was observed in lung infiltrated only by LBLa cell line. NF-kappaB activation was evaluated to determine whether differential activity of MMP-9 was dependent on downstream signaling pathway, showing higher NF-kappaB activity in the more aggressive LBLa cell line. Our results showed that MMP-9 activity modulated by HA through NF-kappaB signaling pathway may be involved in the aggressive behavior of LBLa.
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PMID:Modulation of matrix metalloproteinase-9 activity by hyaluronan is dependent on NF-kappaB activity in lymphoma cell lines with dissimilar invasive behavior. 1547 89

We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, Kd-restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes.
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PMID:Inhibition of membrane type-1 matrix metalloproteinase by cancer drugs interferes with the homing of diabetogenic T cells into the pancreas. 1594 63


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