Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phospholipase C-? in immune cells.

ABSTRACT: Great progress has recently been made in structural and functional research of phospholipase C (PLC)-?. We now understand how PLC-? isoforms (?1-?4) are activated by GTP-bound G?q downstream of G protein-coupled receptors. Numerous studies indicate that PLC-?s participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-?3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein-tyrosine phosphatase SHP-1, with which PLC-?3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation.

SUBMITTER: Kawakami T

PROVIDER: S-EPMC4324595 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Phospholipase C-β in immune cells.

Kawakami Toshiaki T Xiao Wenbin W

Advances in biological regulation 20130814 3

Great progress has recently been made in structural and functional research of phospholipase C (PLC)-β. We now understand how PLC-β isoforms (β1-β4) are activated by GTP-bound Gαq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-βs participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-β3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by re ...[more]

PMID: 23981313

Similar Datasets

Structural insights into phospholipase C-β function.

Project description:Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. The production of these molecules promotes the release of intracellular calcium and activation of protein kinase C, which results in profound cellular changes. The PLCβ subfamily is of particular interest given its prominent role in cardiovascular and neuronal signaling and its regulation by G protein-coupled receptors, as PLCβ is the canonical downstream target of the heterotrimeric G protein Gαq. However, this is not the only mechanism regulating PLCβ activity. Extensive structural and biochemical evidence has revealed regulatory roles for autoinhibitory elements within PLCβ, Gβγ, small molecular weight G proteins, and the lipid membrane itself. Such complex regulation highlights the central role that this enzyme plays in cell signaling. A better understanding of the molecular mechanisms underlying the control of its activity will greatly facilitate the search for selective small molecule modulators of PLCβ.

| S-EPMC3781385 | biostudies-literature

Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells.

Project description:Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis.

| S-EPMC4516794 | biostudies-literature

Role of phospholipase C-β in RNA interference.

Project description:Phospholipase C-β (PLCβ) enzymes are activated by G proteins in response to agents such as hormones and neurotransmitters, and have been implicated in leukemias and neurological disorders. PLCβ activity causes an increase in intracellular calcium which ultimately leads to profound changes in the cell. PLCβ localizes to three cellular compartments: the plasma membrane, the cytosol and the nucleus. Under most cell conditions, the majority of PLCβ localizes to the plasma membrane where it interacts with G proteins. In trying to determine the factors that localize PLCβ to the cytosol and nucleus, we have recently identified the binding partner, TRAX. TRAX is a nuclease and part of the machinery involved in RNA interference. This review discusses the interaction between PLCβ and TRAX, and its repercussions in G protein signaling and RNA silencing.

| S-EPMC3805765 | biostudies-literature

Membrane-induced allosteric control of phospholipase C-β isozymes.

Project description:All peripheral membrane proteins must negotiate unique constraints intrinsic to the biological interface of lipid bilayers and the cytosol. Phospholipase C-β (PLC-β) isozymes hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to propagate diverse intracellular responses that underlie the physiological action of many hormones, neurotransmitters, and growth factors. PLC-β isozymes are autoinhibited, and several proteins, including Gαq, Gβγ, and Rac1, directly engage distinct regions of these phospholipases to release autoinhibition. To understand this process, we used a novel, soluble analog of PIP2 that increases in fluorescence upon cleavage to monitor phospholipase activity in real time in the absence of membranes or detergents. High concentrations of Gαq or Gβ1γ2 did not activate purified PLC-β3 under these conditions despite their robust capacity to activate PLC-β3 at membranes. In addition, mutants of PLC-β3 with crippled autoinhibition dramatically accelerated the hydrolysis of PIP2 in membranes without an equivalent acceleration in the hydrolysis of the soluble analog. Our results illustrate that membranes are integral for the activation of PLC-β isozymes by diverse modulators, and we propose a model describing membrane-mediated allosterism within PLC-β isozymes.

| S-EPMC4207972 | biostudies-literature

Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells.

Project description:To examine the role of group VIA phospholipase A2 (iPLA2?) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2? deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2?-KO), or in insulin-secreting ?-cells (?-Cell-iPLA2?-KO), respectively. MØ-iPLA2?-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2? control mice after consuming a high-fat diet (HFD). MØ-iPLA2?-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2?-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, ?-cell-iPLA2?-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. ?-Cell-iPLA2?-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. ?-Cell-iPLA2?-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2? participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, ?-cell iPLA2? plays a role in GSIS and also appears to confer some protection against deterioration in ?-cell functions induced by a HFD.

| S-EPMC7602969 | biostudies-literature

Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation.

Project description:Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)beta) localizes in and protects beta-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA(2)beta-null (iPLA(2)beta(-/-)) mice to investigate the role of iPLA(2)beta in the repair of mitochondrial membranes. We show that islets isolated from iPLA(2)beta(-/-) mice are more sensitive to staurosporine-induced apoptosis than those from wild-type littermates and that 2 wk of daily ip administration of staurosporine to iPLA(2)beta(-/-) mice impairs both the animals' glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA(2)beta inhibitor bromoenol lactone caused mitochondrial membrane peroxidation and cytochrome c release, and these effects were reversed by N-acetyl cysteine. The mitochondrial antioxidant N-t-butyl hydroxylamine blocked staurosporine-induced cytochrome c release and caspase-3 activation in iPLA(2)beta(-/-) islets. Furthermore, the collapse of mitochondrial membrane potential in INS-1 insulinoma cells caused by high glucose and fatty acid levels was attenuated by overexpressing iPLA(2)beta. Interestingly, iPLA(2)beta was expressed only at low levels in islet beta-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA(2)beta is important in repairing oxidized mitochondrial membrane components (e.g. cardiolipin) and that this prevents cytochrome c release in response to stimuli that otherwise induce apoptosis. The low iPLA(2)beta expression level in db/db mouse beta-cells may render them vulnerable to injury by reactive oxygen species.

| S-EPMC2903934 | biostudies-literature

Downregulation of miRNA-26 in chronic periodontitis interferes with innate immune responses and cell migration by targeting phospholipase C beta 1.

Project description:AimTo evaluate the potential role of miR-26 family members in periodontal pathogenesis by assessing innate immune responses to periopathic bacteria and regulation of cytoskeletal organization.Materials and methodsExpression of miR-26a-5p and miR-26b-5p was quantified in gingival biopsies derived from healthy and periodontally diseased subjects before and after non-surgical (scaling and root planing) therapy by RT-qPCR. Global pathway analysis and luciferase assays were performed for target identification and validation. Cytokine expression was assessed in miR-26a-5p transfected human oral keratinocytes upon stimulation with either live Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans or Pg lipopolysaccharide (LPS). Wound closure assays were performed in cells transfected with miR-26a-5p, while the impact on cytoskeletal organization was assessed by F-actin staining.ResultsmiR-26a-5p and miR-26b-5p were downregulated in diseased gingiva and restored 4-6 weeks post-therapy to levels comparable with healthy subjects. Target validation assays identified phospholipase C beta 1 as a bona fide novel target exhibiting antagonistic expression pattern in disease and post-therapy cohorts. miR-26a-5p transfected cells secreted higher levels of cytokine/chemokines upon stimulation with periopathogens and demonstrated impaired cell migration and cytoskeletal rearrangement.ConclusionsDownregulated miR-26a-5p levels in periodontal inflammation may interfere with key cellular functions that may have significant implications for host defence and wound healing.

| S-EPMC10087579 | biostudies-literature

Role of calcium-independent phospholipase A(2)β in human pancreatic islet β-cell apoptosis.

Project description:Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA(2)β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA(2)β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA(2)β message, protein, and activity, iPLA(2)β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA(2)β protein in human islet β-cells and that induction of iPLA(2)β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA(2)β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.

| S-EPMC3774083 | biostudies-literature

Therapeutic Strategies for Diabetes: Immune Modulation in Pancreatic β Cells.

Project description:Increased incidence of type I and type II diabetes has been prevailed worldwide. Though the pathogenesis of molecular mechanisms remains still unclear, there are solid evidence that disturbed immune homeostasis leads to pancreatic β cell failure. Currently, autoimmunity and uncontrolled inflammatory signaling pathways have been considered the major factors in the pathogenesis of diabetes. Many components of immune system have been reported to implicate pancreatic β cell failure, including helper T cells, cytotoxic T cells, regulatory T cells and gut microbiota. Immune modulation of those components using small molecules and antibodies, and fecal microbiota transplantation are undergoing in many clinical trials for the treatment of type I and type II diabetes. In this review we will discuss the basis of molecular pathogenesis focusing on the disturbed immune homeostasis in type I and type II diabetes, leading to pancreatic β cell destruction. Finally, we will introduce current therapeutic strategies and clinical trials by modulation of immune system for the treatment of type I and type II diabetes patients.

| S-EPMC8415970 | biostudies-literature

Differential distribution of phospholipase C beta isoforms and diaglycerol kinase-beta in rodents cerebella corroborates the division of unipolar brush cells into two major subtypes.

Project description:Sublineage diversification of specific neural cell classes occurs in complex as well as simply organized regions of the central and peripheral nervous systems; the significance of the phenomenon, however, remains insufficiently understood. The unipolar brush cells (UBCs) are glutamatergic cerebellar interneurons that occur at high density in vestibulocerebellum. As they are classified into subsets that differ in chemical phenotypes, intrinsic properties, and lobular distribution, they represent a valuable neuronal model to study subclass diversification. In this study, we show that cerebellar UBCs of adult rats and mice form two subclasses-type I and type II UBCs-defined by somatodendritic expression of calretinin (CR), mGluR1α, phospholipases PLCβ1 and PLCβ4, and diacylglycerol kinase-beta (DGKβ). We demonstrate that PLCβ1 is associated only with the CR(+) type I UBCs, while PLCβ4 and DGKβ are exclusively present in mGluR1α(+) type II UBCs. Notably, all PLCβ4(+) UBCs, representing about 2/3 of entire UBC population, also express mGluR1α. Furthermore, our data show that the sum of CR(+) type I UBCs and mGluR1α(+) type II UBCs accounts for the entire UBC class identified with Tbr2 immunolabeling. The two UBC subtypes also show a very different albeit somehow overlapping topographical distribution as illustrated by detailed cerebellar maps in this study. Our data not only complement and extend the previous knowledge on the diversity and subclass specificity of the chemical phenotypes within the UBC population, but also provide a new angle to the understanding of the signaling networks in type I and type II UBCs.

| S-EPMC3714372 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data