Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stromelysin is a metalloproteinase with the widest substrate specificity that plays a critical role in the induction of the metastatic phenotype in cancer cells. The mechanisms whereby growth factors and oncogenes control stromelysin expression are beginning to be characterized. We have recently demonstrated that protein kinase C isotypes down-regulatable by chronic exposure to phorbol esters are not involved in stromelysin gene expression in response to platelet-derived growth factor, ras oncogene, and phosphatidylcholine-hydrolyzing phospholipase C. We also identified a region in the stromelysin promoter, distinct from the 12-O-tetradecanoylphorbol-13-acetate-responsive element, responsible for the promoter activity in response to these stimulants. In this paper, we further characterize that promoter fragment and demonstrate that the region encompassing nucleotides -1218 to -1202, including the palindromic sequence ACTAGT, is necessary and sufficient for the control of stromelysin gene expression. The involvement of zeta-protein kinase C but not of c-raf in the stimulation of stromelysin promoter activity in response to platelet-derived growth factor is also demonstrated here. All these data suggest the existence of a bifurcation downstream of ras in the signaling mechanisms leading to stromelysin expression and DNA synthesis.
...
PMID:Zeta PKC plays a critical role during stromelysin promoter activation by platelet-derived growth factor through a novel palindromic element. 814 3

Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] are common in osteoarthritis knee effusions, and are often associated with low-grade synovial proliferation and inflammation. Calcium-containing crystals including HA, are known to have a number of biologic effects on culture cells such induction of mitogenesis, stimulation of Prostaglandin E2 (PGE2) production via the phospholipase A2/cyclo-oxygenase pathway, activation of phospholipase C and inositol phospholipid hydrolysis, induction of metalloproteinase synthesis and induction of proto-oncogenes (c-fos and c-myc). While endocytosis of HA particles is prerequisite of the mitogenic effect of calcium-containing crystals in fibroblasts, it is not known whether endocytosis is required for crystal-induced metalloproteinase synthesis. In the present series of experiments, we examine the effect of three different sizes (106, 46, and 17 microns mean diameters) well-characterized spherical HA particles on the induction of mitogenesis and metalloproteinase synthesis on human fibroblasts. We showed that endocytosis is required for HA particles to induce synthesis of metalloproteinases.
...
PMID:Calcium phosphate particle induction of metalloproteinase and mitogenesis: effect of particle sizes. 921 77

Our prior work shows that cultured BR cells derived from dog mastocytomas secrete the 92-kDa proenzyme form of gelatinase B. We provided a possible link between mast cell activation and metalloproteinase-mediated matrix degradation by demonstrating that alpha-chymase, a serine protease released from secretory granules by degranulating mast cells, converts progelatinase B to an enzymatically active form. The current work shows that these cells also secrete gelatinase A. Furthermore, gelatinases A and B both colocalize to alpha-chymase-expressing cells of canine airway, suggesting that normal mast cells are a source of gelatinases in the lung. In BR cells, gelatinase B and alpha-chymase expression are regulated, whereas gelatinase A expression is constitutive. Progelatinase B mRNA and enzyme expression are strongly induced by the critical mast cell growth factor, kit ligand, which is produced by fibroblasts and other stromal cells. Induction of progelatinase B is blocked by U-73122, Ro31-8220, and thapsigargin, implicating phospholipase C, protein kinase C, and Ca2+, respectively, in the kit ligand effect. The profibrotic cytokine TGF-beta virtually abolishes the gelatinase B mRNA signal and also attenuates kit ligand-mediated induction of gelatinase B expression, suggesting that an excess of TGF-beta in inflamed or injured tissues may alter mast cell expression of gelatinase B, which is implicated in extracellular matrix degradation, angiogenesis, and apoptosis. In summary, these data provide the first evidence that normal mast cells express gelatinases A and B and suggest pathways by which their regulated expression by mast cells can influence matrix remodeling and fibrosis.
...
PMID:Mast cell expression of gelatinases A and B is regulated by kit ligand and TGF-beta. 1022 34

Among the five membrane-type matrix metalloproteinases (MT-MMPs), MT1-, MT2-, MT3-, and MT5-MMPs have about a 20-amino acid cytoplasmic tail following the transmembrane domain. In contrast, a putative transmembrane domain of MT4-MMP locates at the very C-terminal end, and the expected cytoplasmic tail is very short or nonexistent. Such sequences often act as a glycosylphosphatidylinositol (GPI) anchoring signal rather than as a transmembrane domain. We thus examined the possibility that MT4-MMP is a GPI-anchored proteinase. Our results showed that [(3)H]ethanolamine, which can be incorporated into the GPI unit, specifically labeled the MT4-MMP C-terminal end in a sequence-dependent manner. In addition, phosphatidylinositol-specific phospholipase C treatment released the MT4-MMP from the surface of transfected cells. These results indicate that MT4-MMP is the first GPI-anchored proteinase in the MMP family. During cultivation of the transfected cells, MT4-MMP appeared to be shed from the cell surface by the action of an endogenous metalloproteinase. GPI anchoring of MT4-MMP on the cell surface indicates a unique biological function and character for this proteinase.
...
PMID:Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositol-anchored proteinase. 1056

A comparative study of proteolytic enzymes and cell-surface protein composition in virulent and avirulent Leishmania (Leishmania) amazonensis promastigote forms was carried out using one- and two-dimensional dodecyl sulfate sodium-polyacrylamide gel electrophoresis (SDS-PAGE). The surface iodinated protein profiles showed two major polypeptides of 65-60 and 50-47 kDa that were expressed in both virulent and avirulent promastigote forms. However, minor quantitative differences were observed in the cell-surface profile between the avirulent and virulent promastigotes. These included polypeptides of 115, 52, 45, 32, and 25 kDa that were preferentially expressed in the virulent forms. Two-dimensional SDS-PAGE showed an accentuated expression of acidic polypeptides; some of them differentially expressed in the promastigote forms analyzed. Live parasites treated with glycosylphosphatidylinositol (GPI)-specific phospholipase C (PLC) from Trypanosoma brucei and immunoprecipitated with the cross-reacting determinant (CRD) antibody recognized three major polypeptides of 65-60, 52, and 50-47 kDa, hence suggesting that these peptides were anchored to the plasma membrane domains through GPI anchor. Moreover, the polypeptides of 65-60 and 52 kDa were also recognized by the gp63 antiserum. Several metalloproteinase activities were similar in both virulent and avirulent promastigote forms, whereas cysteine proteinase activities, sensitive to E-64, were preferentially expressed in virulent promastigotes. These results suggest that cell-surface polypeptides and intracellular cysteine proteinases might play an important role in the virulence of L. (L.) amazonensis.
...
PMID:Leishmania (Leishmania) amazonensis: differential expression of proteinases and cell-surface polypeptides in avirulent and virulent promastigotes. 1455 57

C-terminal truncation of ADAMTS-4 from the p68 form to the p53 form is required for activation of its capacity to cleave the Glu(373)-Ala(374) interglobular domain bond of aggrecan. In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1. Instead, activation can be mediated by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase (MT4-MMP, MMP-17) because co-transfection with the active form of MT4-MMP markedly enhanced activation, whereas an inactive mutant of MT4-MMP was ineffective. Treatment of co-transfected cells with phosphatidylinositol-specific phospholipase C liberated the complex of MT4-MMP and p68 ADAMTS4 from the cell membrane, but the p53 ADAMTS4 remained associated. Specific glycosaminoglycan lyase digestions, followed by product analyses using fluorescence-assisted carbohydrate electrophoresis and immunoprecipitation experiments, showed that the p53 form is associated with syndecan-1 through both chondroitin sulfate and heparan sulfate. We conclude that ADAMTS-4 activation in this cell system involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface.
...
PMID:ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. 1470 64

1.--Thrombin is activated during gingival tissue injury and inflammation. Thrombin (platelet)-rich plasma has been used for periodontal regeneration with success. Thrombin and other bacterial proteases also affect the functions of adjacent periodontal cells via stimulation of protease-activated receptors (PARs). 2.--We noted that thrombin (0.1-2 U ml(-1)), human, and frog PAR-1 agonist peptide (20-240 microM) induced the gingival fibroblast (GF)-populated collagen gel contraction within 2 h of exposure. However, PAR-2, PAR-3, and PAR-4 agonist peptide (20-240 microM) showed little effect on collagen gel contraction. U73122 (phospholipase C inhibitor) and 2-APB (IP3 antagonist) were effective in inhibition of GF contraction. 3.--Thrombin-induced GF contraction was inhibited by 5 mM EGTA (an extracellular calcium chelator) and verapamil (an L-type calcium channel blocker). In addition, W7 (10 and 25 microM, a calcium/calmodulin (CaM) inhibitor), ML-7 (50 microM, myosin light chain kinase (MLCK) inhibitor), and HA1077 (100 microM, Rho kinase inhibitor) completely inhibited the thrombin-induced collagen gel contraction. Thrombin also induced the phosphorylation of ERK1/ERK2 and elevated the Rho-GTP levels in GF. 4.--However, U0126 only partially inhibited the thrombin-induced GF contraction. Similarly, wortmannin (100 nM), LY294002 (20 microM) (two PI3K inhibitor) and genistein also showed partial inhibition. Moreover, NAC was not able to suppress the GF contraction, as supported by the slight decrease in reactive oxygen species production in GF by thrombin. 5.--Thrombin also stimulated metalloproteinase-2 (MMP-2) and MMP-3 production in GF. But addition of GM6001 or 1,10-phenanthroline, two MMP inhibitors, could not inhibit the thrombin-induced GF contraction. 6.--These results indicate that thrombin is crucial in the periodontal inflammation and wound healing by promoting GF contraction. This event is mainly mediated via PAR-1 activation, PLC activation, extracellular calcium influx via L-type calcium channel, and the calcium/CaM-MLCK and Rho kinase activation pathway.
...
PMID:Signaling mechanism of thrombin-induced gingival fibroblast-populated collagen gel contraction. 1629 51

In this work we have investigated the ability of epinephrine to trigger the release of intracellular Ca2+ in thrombin-desensitized platelets. Addition of thrombin to platelets in the presence of extracellular EGTA caused a rapid and transient release of Ca2+ from intracellular stores and rendered platelets unresponsive to a second addition of the same agonist. Although epinephrine alone had no effect on intracellular Ca2+ mobilization, its addition to thrombin-desensitized platelets was associated to a rapid and evident secondary release of intracellular Ca2+. This effect of epinephrine was not observed when platelets were desensitized with other agonists able to induce phospholipase C activation, including convulxin, U46619, and ADP. Although the platelet receptor for epinephrine is coupled to the Gi family member Gz, no secondary Ca2+ release was seen in thrombin-desensitized platelets upon stimulation of other Gi-coupled receptors, including the P2Y12 receptor and the CXCR4. Addition of hirudin to thrombin-desensitized platelets prevented epinephrine-promoted secondary release of Ca2+, indicating that thrombin, rather than epinephrine itself, is actually responsible for this event as a consequence of thrombin receptors resensitization. Studies with platelets stimulated with specific PAR1- and PAR4- activating peptides proved that neither one of these thrombin receptors were involved in the secondary epinephrine-assisted Ca2+ release. Moreover, we found that thrombin was still able to induce a reduced, but evident release of Ca2+ from internal stores in PAR1- and PAR4-desensitized platelets, which could be followed by a secondary Ca2+ release upon subsequent addition of epinephrine. Importantly, both the primary and the secondary Ca2+ release induced by thrombin and epinephrine in PAR1- and PAR4-desensitized platelets were abrogated upon cleavage of GPIbalpha by the metalloproteinase mocarhagin. These results demonstrate a direct role of thrombin binding to GPIb-IX-V in the mobilization of Ca2+ from intracellular stores, and reveal that epinephrine can restore this process in desensitized platelets, thus prolonging the effect of thrombin stimulation.
...
PMID:Epinephrine induces intracellular Ca2+ mobilization in thrombin-desensitized platelets: a role for GPIb-IX-V. 1736 62

Vasopressin acts on astrocytic Gq protein- and phospholipase C-coupled V1 receptors. In mesangial cells, which also express the V1 receptor, it stimulates cell growth by activating mitogen-activated protein kinase (MAP kinase) secondary to transactivation of the epidermal growth factor (EGF) receptor. Transactivation is an intracellular/extracellular process, in which activation of a Gq or a Gi/o protein-coupled receptor leads to metalloproteinase-catalyzed shedding of an EGF receptor agonist, which stimulates EGF receptors on the same cell and/or its neighbor(s). The goal of the present study was to investigate if vasopressin signaling is mediated by transactivation also in astrocytes and whether such a transactivation is required for its ability to facilitate vector-driven water fluxes. Vasopressin concentrations between 10(-12) and 10(-6) M were found to lead to phosphorylation (activation) of extracellular regulated kinase 1 and 2 (ERK 1/2). Phosphorylation of ERK 1/2 could be completely inhibited by either AG1478, an inhibitor of the EGF receptor-activated tyrosine kinase, or GM6001, an inhibitor of Zn2+-activated metalloproteinases, indicating the involvement of transactivation. Exposure to a hypotonic medium caused an immediate (within one min) increase in cell water volume (demonstrated by decrease of fluorescence quenching of calcein), part of which was dependent upon the presence of vasopressin, added at a concentration of 1 x 10(-8) M. This vasopressin-dependent component persisted throughout the duration of the experiment (22 min). The effect of vasopressin was abolished in the presence of AG1478, indicating its dependence upon transactivation, and by U0126 an inhibitor of the MAP kinase/ERK kinase (MEK), and thus of ERK 1/2 phosphorylation.
...
PMID:Stimulation by vasopressin of ERK phosphorylation and vector-driven water flux in astrocytes is transactivation-dependent. 1848 26

CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. On the other hand, the effect of CCL5 is mediated via CCR receptor. RT-PCR and flow cytometry studies demonstrated CCR5 but not CCR1 and CCR3 mRNA in oral cancer cell lines, especially higher in those with high invasiveness (SCC4) as compared with lower levels in HSC3 cells and SCC9 cells. Stimulation of oral cancer cells with CCL5 directly increased the migration and metalloproteinase-9 (MMP-9) production. MMP-9 small interfering RNA inhibited the CCL5-induced MMP-9 expression and thereby significantly inhibited the CCL5-induced cell migration. Activations of phospholipase C (PLC), protein kinase Cdelta (PKCdelta), and NF-kappaB pathways after CCL5 treatment was demonstrated, and CCL5-induced expression of MMP-9 and migration activity was inhibited by the specific inhibitor of PLC, PKCdelta, and NF-kappaB cascades. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-9, CCL5, and CCR5. Taken together, these results indicate that CCL5/CCR5 axis enhanced migration of oral cancer cells through the increase of MMP-9 production.
...
PMID:CCL5/CCR5 axis promotes the motility of human oral cancer cells. 1933 35


1 2 Next >>

---