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)

Membrane type 1-matrix metalloproteinase (MT1-MMP) has been suggested to play an important role in angiogenesis, but the mechanisms involved remain incompletely understood. Using an in vitro model of angiogenesis in which cell migration of bovine aortic endothelial cells (BAECs) and their morphogenic differentiation into capillary-like structures on Matrigel are induced by overexpression of MT1-MMP, we show that the platelet-derived bioactive lipid sphingosine 1-phosphate (S1P) is the predominant serum factor essential for MT1-MMP-dependent migration and morphogenic differentiation activities. In the presence of S1P, MT1-MMP-dependent cell migration and morphogenic differentiation were inhibited by pertussis toxin, suggesting the involvement of Gi-protein-coupled receptor-mediated signaling. Accordingly, cotransfection of BAECs with MT1-MMP and a constitutively active Galphai2 (Q205L) mutant increased cell migration and morphogenic differentiation, whereas treatment of BAECs overexpressing MT1-MMP with antisense oligonucleotides directed against S1P1 and S1P3, the predominant S1P receptors, significantly inhibited both processes. These results demonstrate that MT1-MMP-induced migration and morphogenic differentiation involve the cooperation of the enzyme with platelet-derived bioactive lipids through S1P-mediated activation of Galphai-coupled S1P1 and S1P3 receptors. Given the important contribution of platelets to tumor angiogenesis, the stimulation of endothelial MT1-MMP function by S1P may thus constitute an important molecular event linking hemostasis to angiogenesis.
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PMID:Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation. 1507 Jun 79

Membrane type 1 matrix metalloproteinase (MT1-MMP) is a transmembrane MMP that plays important roles in migratory processes underlying tumor invasion and angiogenesis. In addition to its matrix degrading activity, MT1-MMP also contains a short cytoplasmic domain whose involvement in cell locomotion seems important but remains poorly understood. In this study, we show that MT1-MMP is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (Tyr(573)) and that this phosphorylation requires the kinase Src. Using phosphospecific antibodies recognizing MT1-MMP phosphorylated on Tyr(573), we observed that tyrosine phosphorylation of the enzyme is rapidly induced upon stimulation of tumor and endothelial cells with the platelet-derived chemoattractant sphingosine-1-phosphate, suggesting a role in migration triggered by this lysophospholipid. Accordingly, overexpression of a nonphosphorylable MT1-MMP mutant (Y573F) blocked sphingosine-1-phosphate-induced migration of Human umbilical vein endothelial cells and HT-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). Altogether, these findings strongly suggest that the Src-dependent tyrosine phosphorylation of MT1-MMP plays a key role in cell migration and further emphasize the importance of the cytoplasmic domain of the enzyme in this process.
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PMID:Src-dependent phosphorylation of membrane type I matrix metalloproteinase on cytoplasmic tyrosine 573: role in endothelial and tumor cell migration. 1738

Prostate cancer commonly affects men in the Western world. A major factor of the life-threatening course of this disease is the high rate of metastasis, predominantly to bones. Circulating tumor cells encounter platelets and may activate them, resulting in a production of microparticles (MPs). MPs are small platelet fragments expressing membrane receptors as well as cytoplasmic constituents. Here, we report that prostate cancer cells, Clone-1 (Cl-1), preincubated with platelet-derived MPs (PMPs), demonstrate increased invasion through a gelatin-coated (a denatured form of collagen) membrane of the Boyden chamber system. This effect was accompanied by an increased secretion of metalloproteinase-2 (MMP-2) as demonstrated by a gelatin zymography. Application of MMP-2/9 inhibitor reversed the PMP-induced tumor cell invasion. PMPs were shown to adhere to Cl-1 cells, but direct contact between them may not be mandatory for MMP secretion because PMP lysate induced MMP-2 production by Cl-1 cells to the same extent as did intact PMPs. PMP-induced MMP-2 secretion was inhibited by neutralization of either PKC or total intracellular tyrosine phosphorylation, but was not affected by blocking major intraplatelet cytokines. Actinomycin D (a transcription inhibitor) did not modify this effect, whereas cycloheximide (an inhibitor of protein translation) abolished the MMP-2 release. MMP-2 secretion was accompanied by a rapid and transient increase in MMP-2 mRNA level after a 2-hr coincubation of prostate cancer cells with PMPs. Thus, PMPs promote tumor invasiveness, at least in part by stimulation of MMP-2 production.
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PMID:Platelet-derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP-2 production. 1910 87