Phosphoinositide and Inositol Phosphate Analysis in Lymphocyte Activation

Sauer, Karsten; Huang, Yina H.; Lin, Hongying; Sandberg, Mark L.; Mayr, Georg W.

doi:10.1002/0471142735.im1101s87

Cited by 23 publications

(32 citation statements)

References 136 publications

(440 reference statements)

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“…For example, T or B cell receptor (TCR or BCR) stimulation activates phospholipases Cγ (PLCγ1, PLCγ2), which then hydrolyse membrane PtdIns(4,5) P 2 into two second messenger molecules: the membrane-lipid diacylglycerol (DAG) and soluble Ins P 3 (Fig. 1)25–28. DAG recruits and activates key signalling mediators such as the RAS-activator RASGRP1 and protein kinases C (PKCs).…”

Section: Inositols In Immunoreceptor Signallingmentioning

confidence: 99%

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

2010

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Preface The membrane lipid phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential functions for the soluble PtdInsP3 analogue inositol(1,3,4,5)tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in immunocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

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Section: Inositols In Immunoreceptor Signallingmentioning

confidence: 99%

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

2010

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“…For activation of ITPK by Ca 2ϩ /calmodulin (CaM), 2.15 g/ml calmodulin and 10 -20 M free CaCl 2 were in the assay mixture. Samples were treated for HPLC analysis as described previously (20), and Ins(1,4,5)P 3 and its metabolites Ins(1,3,4,5)P 4 , Ins(1,3,4)P 3 , and Ins(1,3,4,6)P 4 were analyzed by Micro MDD-HPLC as described previously (24). Total ITPK activity was determined for individual intervals as the sum of the rates of formation of Ins(1,3,4,5)P 4 , Ins(1,3,4)P 3 , and Ins(1,3,4,6)P 4 .…”

Section: Determination Of Migratory Potential Of Tumor Cell Lines In mentioning

confidence: 99%

Inositol 1,4,5-Trisphosphate 3-Kinase-A Is a New Cell Motility-promoting Protein That Increases the Metastatic Potential of Tumor Cells by Two Functional Activities

Windhorst

Fliegert

Blechner

et al. 2010

Journal of Biological Chemistry

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The formation of distant metastases is a complex process involving escape of cancer cells from the primary tumor, dissemination to distant organs, and finally re-colonization and expansion (1). For metastatic dissemination, the cancer cell must acquire the ability to migrate, which is associated with cytoskeletal re-arrangements. Migrating cells extend actinbased filopodia and lamellipodia at the leading edge. To initiate this process, a local formation of F-actin is required, which can be mediated by actin nucleating (e.g. Arp2/3 and formins (2)), F-actin bundling (e.g. fascin (3)), and by F-actin cross-linking proteins (e.g. filamins (4)). The actin-severing proteins ADF/ cofilin and gelsolin depolymerize F-actin and thus increase actin turnover (5). The balance between stimulation of actinpolymerizing proteins and actin-depolymerizing proteins is tightly regulated by distinct signaling pathways (e.g. phospholipase C and phosphoinositide 3-kinase (6 -8)). As activation of these pathways can also result in induction of proliferation, "fine-tuning" of continuous signal inputs determines the cellular response. This fine-tuning is mediated by various small molecules, including calcium, cyclic AMP, phosphatidylinositol phosphates, and inositol phosphates. Among the inositides, membranous phosphatidylinositol 4,5-bisphosphate plays a central role in the control of migration as it regulates the activity of cofilin, gelsolin, and profilin (9, 10) and serves as a substrate for the production of the calcium-mobilizing second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ).2 Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate increases Ins(1,4,5)P 3 levels and subsequent calcium release from the endoplasmic reticulum. Calcium plays an important role in cell migration because calcium transients activate gelsolin and indirectly ADF/cofilin (9, 10).Inositol 1,4,5-trisphosphate 3-kinase isoenzymes (ITPKA, ITPKB, and ITPKC) metabolize Ins(1,4,5)P 3 to inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P 4 ), and thus regulate Ins(1,4,5)P 3 -induced calcium signals (11). The ITPK isoenzymes are highly conserved in their catalytically active C-terminal domains but show large differences in their N-terminal regulatory domains mediating mainly cellular targeting. The isoenzymes differ in subcellular localization and tissue expression patterns. ITPKB and ITPKC mRNAs are ubiquitously expressed, whereas mRNA of ITPKA was only identified in neurons and testis (12). In neurons, ITPKA was shown to be targeted to F-actin via an N-terminal actin binding domain (amino acids 1-66 (13)) and was suggested to be relevant for long term potentiation and spatial learning (14,15

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“…[ 3 H]-IP 3 is quantified following purification on anion-exchange chromatography or by HPLC [51,52]. HPLC also allows quantification of the production of the other inositol phosphates [53]. As for cAMP, specific IP 3 antibodies allowed development of several specific and sensitive immunoassays.…”

Section: H]myo-inositol Is Incorporated Into Intact Cells As [ 3 H]-mentioning

confidence: 99%

Probing Heterotrimeric G Protein Activation: Applications to Biased Ligands

Denis

Saulière

Galandrin

et al. 2012

CPD

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Cell surface G protein-coupled receptors (GPCRs) drive numerous signaling pathways involved in the regulation of a broad range of physiologic processes. Today, they represent the largest target for modern drugs development with potential application in all clinical fields. Recently, the concept of "ligand-directed trafficking" has led to a conceptual revolution in pharmacological theory, thus opening new avenues for drug discovery. Accordingly, GPCRs do not function as simple on-off switch but rather as filters capable of selecting the activation of specific signals and thus generating texture responses to ligands, a phenomenon often referred to as ligand-biased signaling. Also, one challenging task today remains optimization of pharmacological assays with increased sensitivity so to better appreciate the inherent texture of ligands. However, considering that a single receptor has pleiotropic signaling properties and that each signal can crosstalk at different levels, biased activity remains thus difficult to evaluate. One strategy to overcome these limitations would be examining the initial steps following receptor activation. Even, if some G protein independent functions have been recently described, heterotrimeric G protein activation remains a general hallmark for all GPCRs families and the first cellular event subsequent to agonist binding to the receptor. Herein, we review the different methodologies classically used or recently developed to monitor G protein activation and discussed them in the context of G protein biased-ligands.

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Phosphoinositide and Inositol Phosphate Analysis in Lymphocyte Activation

Cited by 23 publications

References 136 publications

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Inositol 1,4,5-Trisphosphate 3-Kinase-A Is a New Cell Motility-promoting Protein That Increases the Metastatic Potential of Tumor Cells by Two Functional Activities

Probing Heterotrimeric G Protein Activation: Applications to Biased Ligands

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