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

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

The conceptual segregation of G protein-stimulated cell signaling responses into those mediated by heterotrimeric G proteins versus those promoted by small GTPases of the Ras superfamily is no longer vogue. PLC-epsilon, an isozyme of the phospholipase C (PLC) family, has been identified recently and dramatically extends our understanding of the crosstalk that occurs between heterotrimeric and small monomeric GTPases. Like the widely studied PLC-beta isozymes, PLC-epsilon is activated by Gbetagamma released upon activation of heterotrimeric G proteins. However, PLC-epsilon markedly differs from the PLC-beta isozymes in its capacity for activation by Galpha(12/13) - but not Galpha(q) -coupled receptors. PLC-epsilon contains two Ras-associating domains located near the C terminus, and H-Ras regulates PLC-epsilon as a downstream effector. Rho also activates PLC-epsilon, but in a mechanism independent of the C-terminal Ras-associating domains. Therefore, Ca(2+) mobilization and activation of protein kinase C are signaling responses associated with activation of both H-Ras and Rho. A guanine nucleotide exchange domain conserved in the N terminus of PLC-epsilon potentially confers a capacity for activators of this isozyme to cast signals into additional signaling pathways mediated by GTPases of the Ras superfamily. Thus, PLC-epsilon is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways.
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PMID:PLC-epsilon: a shared effector protein in Ras-, Rho-, and G alpha beta gamma-mediated signaling. 1499 41

In this study we have investigated hyaluronan (HA)-CD44 interaction with protein kinase N-gamma (PKNgamma), a small GTPase (Rac1)-activated serine/threonine kinase in human keratinocytes. By using a variety of biochemical and molecular biological techniques, we have determined that CD44 and PKNgamma kinase (molecular mass approximately 120 kDa) are physically linked in vivo. The binding of HA to keratinocytes promotes PKNgamma kinase recruitment into a complex with CD44 and subsequently stimulates Rac1-mediated PKNgamma kinase activity. The Rac1-activated PKNgamma in turn increases threonine (but not serine) phosphorylation of phospholipase C (PLC) gamma1 and up-regulates PLCgamma1 activity leading to the onset of intracellular Ca(2+) mobilization. HA/CD44-activated Rac1-PKNgamma also phosphorylates the cytoskeletal protein, cortactin, at serine/threonine residues. The phosphorylation of cortactin by Rac1-PKNgamma attenuates its ability to cross-link filamentous actin in vitro. Further analyses indicate that the N-terminal antiparallel coiled-coil (ACC) domains of PKNgamma interact directly with Rac1 in a GTP-dependent manner. The binding of HA to CD44 induces PKNgamma association with endogenous Rac1 and its activity in keratinocytes. Transfection of keratinocytes with PKNgamma-ACCcDNA reduces HA-mediated recruitment of endogenous Rac1 to PKNgamma and blocks PKNgamma activity. These findings suggest that the PKNgamma-ACC fragment acts as a potent competitive inhibitor of endogenous Rac1 binding to PKNgamma in vivo. Most important, the PKNgamma-ACC fragment functions as a strong dominant-negative mutant that effectively inhibits HA/CD44-mediated PKNgamma phosphorylation of PLCgamma1 and cortactin as well as keratinocyte signaling (e.g. Ca(2+) mobilization and cortactin-actin binding) and cellular functioning (e.g. cell-cell adhesion and differentiation). Taken together, these findings strongly suggest that hyaluronan-CD44 interaction with Rac1-PKNgamma plays a pivotal role in PLCgamma1-regulated Ca(2+) signaling and cortactin-cytoskeleton function required for keratinocyte cell-cell adhesion and differentiation.
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PMID:Hyaluronan-CD44 interaction with Rac1-dependent protein kinase N-gamma promotes phospholipase Cgamma1 activation, Ca(2+) signaling, and cortactin-cytoskeleton function leading to keratinocyte adhesion and differentiation. 1512 40

We recently reported that several Gs-coupled receptors stimulate phospholipase C (PLC)-epsilon via increased formation of cyclic AMP and subsequent activation of the small GTPase Rap2B by the cyclic AMP-activated exchange factor Epac1. Here we show by studies in HEK-293 and N1E-115 neuroblastoma cells that this stimulation induced by Gs-coupled receptors or the direct adenylyl cyclase activator, forskolin, is potently inhibited by Gi-coupled receptors, known to inhibit cyclic AMP formation. PLC inhibition by the overexpressed M2 muscarinic receptor and the endogenously expressed sphingosine-1-phosphate and delta-opioid receptors was fully pertussis toxin-sensitive and accompanied by a reduction in Rap2B activation induced by Gs-coupled receptors. In contrast, Rap2B activation and PLC stimulation induced by membrane-permeable cyclic AMP analogues, including an Epac-specific activator, or PLC stimulation caused by constitutively active Rap2B were not affected by the Gi-coupled receptors. In summary, our data indicate that Gi-coupled receptors can inhibit PLC-epsilon, most likely by suppressing formation of cyclic AMP required for Epac-mediated Rap2B activation.
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PMID:Inhibition of phospholipase C-epsilon by Gi-coupled receptors. 1515 71

We have investigated the cellular distribution of p122RhoGAP, a GTPase-activating protein of Rho small GTPase and an activator of phospholipase C-delta(1). Immunofluorescence studies demonstrated that endogenous p122 is localized at the tips of actin stress fibres and co-localizes with vinculin in normal rat kidney cells. In immunoprecipitation studies, p122 co-precipitated with vinculin, indicating that p122 is localized at the sites of focal adhesion. We have also shown that the N-terminal half of p122 is responsible for this localization. It is conceivable, therefore, that p122 is involved in the reorganization of the actin cytoskeleton and focal adhesions that regulate cell-substratum adhesion and cell migration.
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PMID:A PLCdelta1-binding protein, p122RhoGAP, is localized in focal adhesions. 1550 80

Second messengers generated from membrane lipids play a critical role in signaling and control diverse cellular processes. Despite being one of the most evolutionarily conserved of all the phosphoinositide-specific phospholipase C (PLC) isoforms, a family of enzymes responsible for hydrolysis of the membrane lipid phosphatidylinositol bisphosphate, the mechanism of PLC-delta1 activation is still poorly understood. Here we report a novel regulatory mechanism for PLC-delta1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-delta1. In addition, we have identified a novel IQ type CaM binding motif within the catalytic region of PLC-delta1 that is not found in other PLC isoforms. Binding of CaM at the IQ motif inhibits PLC-delta1 activity, while addition of Ral reverses the inhibition. The overexpression of various Ral mutants in cells potentiates PLC-delta1 activity. Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation.
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PMID:Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. 1581 90

Binding of thrombopoietin (TPO) to the cMpl receptor on human platelets potentiates aggregation induced by a number of agonists, including ADP. In this work, we found that TPO was able to restore ADP-induced platelet aggregation upon blockade of the G(q)-coupled P2Y1 purinergic receptor but not upon inhibition of the G(i)-coupled P2Y12 receptor. Moreover, TPO triggered platelet aggregation upon co-stimulation of G(z) by epinephrine but not upon co-stimulation of G(q) by the thromboxane analogue U46619. Platelet aggregation induced by TPO and G(i) stimulation was biphasic, and cyclooxygenase inhibitors prevented the second but not the first phase. In contrast to ADP, TPO was unable to induce integrin alpha(IIb)beta(3) activation, as evaluated by binding of both fibrinogen and PAC-1 monoclonal antibody. However, ADP-induced activation of integrin alpha(IIb)beta(3) was blocked by antagonists of the G(q)-coupled P2Y1 receptor but was completely restored by the simultaneous co-stimulation of cMpl receptor by TPO. Inside-out activation of integrin alpha(IIb)beta(3) induced by TPO and G(i) stimulation occurred independently of thromboxane A(2) production and was not mediated by protein kinase C, MAP kinases, or Rho-dependent kinase. Importantly, TPO and G(i) activation of integrin alpha(IIb)beta(3) was suppressed by wortmannin and Ly294002, suggesting a critical regulation by phosphatidylinositol 3-kinase. We found that TPO did not activate phospholipase C in human platelets and was unable to restore ADP-induced phospholipase C activation upon blockade of the G(q)-coupled P2Y1 receptor. TPO induced a rapid and sustained activation of the small GTPase Rap1B through a pathway dependent on phosphatidylinositol 3-kinase. In ADP-stimulated platelets, Rap1B activation was reduced, although not abolished, upon blockade of the P2Y1 receptor. However, accumulation of GTP-bound Rap1B in platelets activated by co-stimulation of cMpl and P2Y12 receptor was identical to that induced by the simultaneous ligation of P2Y1 and P2Y12 receptor by ADP. These results indicate that TPO can integrate G(i), but not G(q), stimulation and can efficiently support integrin alpha(IIb)beta(3) activation platelet aggregation by an alternative signaling pathway independent of phospholipase C but involving the phosphatidylinositol 3-kinase and the small GTPase Rap1B.
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PMID:Thrombopoietin complements G(i)- but not G(q)-dependent pathways for integrin {alpha}(IIb){beta}(3) activation and platelet aggregation. 1586 6

Stroke neuroprotection trials suggest that pharmacological manipulations of a single neuroprotective mechanism are generally ineffective and that new approaches, possibly involving simultaneous manipulations of multiple mechanisms, need to be sought. To identify optimal components for such a multipronged approach, we studied NMDA receptor activation-induced cell death in organotypic hippocampal culture preparations as a model of excitotoxicity. Metabotropic group I glutamate receptor (mGluR) activation by their selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), resulted in concentration-dependent reduction of nerve cell susceptibility to NMDA-mediated injury (neuroprotective effect). The neuroprotection was mediated primarily by mGluR1, required phospholipase C activation, was inhibited by cholesterol-containing methyl-beta-cyclodextrin treatment, and occluded by antipsychotic quetiapine. It was associated with suppression of NMDA currents and prolongation of GABA(A) receptor-mediated currents in DHPG-treated cultures. cDNA microarray analysis of 1128 brain-relevant genes revealed that mGluR-mediated neuroprotection was associated with simultaneous activation of endocytosis, and inactivation of inflammation, cell adhesion, cell death, and transcription-related genes. Antisense inhibition of Rab5b, a gene coding for a small GTPase associated with endocytosis, significantly reduced the mGluR-mediated neuroprotection. These findings expand our understanding of the role that mGluRs play in regulation of nerve cell susceptibility to injury and should facilitate the design of novel therapeutic strategies for stroke and other neurodegenerative diseases.
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PMID:Activation of neuroprotective pathways by metabotropic group I glutamate receptors: a potential target for drug discovery? 1617 9

The hypothesis was tested that different chemoattractants have different effects on the activity of integrins expressed by the human eosinophil. Three chemoattractants, CXCL8 (IL-8), CCL11 (eotaxin-1), and C5a were tested with respect to their ability to induce migration and the transition of eosinophils from a rolling interaction to a firm arrest on activated endothelial cells under flow conditions. CCL11 and C5a induced a firm arrest of eosinophils rolling on an endothelial surface, whereas CXCL8 induced only a transient arrest of the cells. The CXCL8- and CCL11-induced arrest was inhibited by simultaneously blocking alpha4 integrins (HP2/1) and beta2 integrins (IB4). In contrast, the C5a-induced arrest was only inhibited by 30% under these conditions. The potency differences of C5a>CCL11>CXCL8 to induce firm adhesion under flow condition was also observed in migration assays and for the activation of the small GTPase Rap-1, which is an important signaling molecule in the inside-out regulation of integrins. Interestingly, only C5a was able to induce the high activation epitope of alphaMbeta2 integrin recognized by MoAb CBRM1/5. The C5a-induced appearance of this epitope and Rap activation was controlled by phospholipase C (PLC), as was shown with the PLC inhibitor U73122. These data show that different chemoattractants are able to induce distinct activation states of integrins on eosinophils and that optimal chemotaxis is associated with the high activation epitope of the alphaMbeta2 integrin. Furthermore, PLC plays an important role in the inside-out signaling and, thus, the activation status of integrins on eosinophils.
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PMID:Differences in potency of CXC chemokine ligand 8-, CC chemokine ligand 11-, and C5a-induced modulation of integrin function on human eosinophils. 1623 5

The involvement of the small GTPase Rap1b in platelet integrin alpha2beta1-dependent outside-in signaling was investigated. Platelet adhesion to 4 different specific ligands for integrin alpha2beta1, monomeric collagen, decorin, and collagen-derived peptides CB8(II) and CB11(II), induced a robust and rapid activation of Rap1b. This process did not require secreted ADP or thromboxane A2 production but was critically regulated by phospholipase C (PLC)-derived second messengers. Both Ca2+ and protein kinase C were found to organize independent but additive pathways for Rap1b activation downstream of integrin-alpha2beta1, which were completely blocked by inhibition of PLC with U73122. Moreover, integrin alpha2beta1 engagement failed to trigger Rap1b activation in murine platelets lacking CalDAG-GEFI, a guanine nucleotide exchange factor regulated by Ca2+ and diacylglycerol, despite normal phosphorylation and activation of PLCgamma2. In addition, CalDAG-GEFI-deficient platelets showed defective integrin alpha2beta1-dependent adhesion and spreading. We found that outside-in signaling through integrin alpha2beta1 triggered inside-out activation of integrin alphaIIbbeta3 and promoted fibrinogen binding. Similarly to Rap1b stimulation, this process occurred downstream of PLC activation and was dramatically impaired in murine platelets lacking the Rap1 exchange factor CalDAG-GEFI. These results demonstrate that Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion and regulates the cross talk between adhesive receptors.
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PMID:The small GTPase Rap1b regulates the cross talk between platelet integrin alpha2beta1 and integrin alphaIIbbeta3. 1635 24

Ral is a multifunctional small GTPase involved in tumorigenesis and in controlling intracellular membrane trafficking. It is mainly activated by factors downstream of Ras, or independently of these factors and operates by protein-protein interactions with an expanding repertoire of partners. RalA is a positive regulator of calcium-evoked exocytosis via binding phospholipase D and is involved in G protein coupled receptor signalling by binding phospholipase C-delta1. The binding of Ral to calmodulin links to intracellular trafficking events. Another link is direct binding of activated Ral (Ral-GTP) to the endocytic and exocytic machineries. Ral-GTP binds RalBP1, which connects to receptor-mediated endocytosis via AP-2. Alternatively, Ral-GTP binds the exocyst complex, which controls secretory vesicle trafficking in regulated secretion and filopodia formation. Thus, Ral-GTP "chooses" between different membrane trafficking pathways. Other Ral partners are still being uncovered that may provide further mechanistic insights into how Ral controls diverse membrane trafficking pathways.
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PMID:Ral: mediator of membrane trafficking. 1678 82


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