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pi(3,4,5)p3

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https://www.readbyqxmd.com/read/28792888/structural-basis-for-interdomain-communication-in-ship2-providing-high-phosphatase-activity
#1
Johanne Le Coq, Marta Camacho-Artacho, José Vicente Velázquez, Clara M Santiveri, Luis Heredia Gallego, Ramón Campos-Olivas, Nicole Dölker, Daniel Lietha
SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain...
August 9, 2017: ELife
https://www.readbyqxmd.com/read/28710365/suppression-of-cell-migration-by-phospholipase-c-related-catalytically-inactive-protein-dependent-modulation-of-pi3k-signalling
#2
Satoshi Asano, Yuri Taniguchi, Yosuke Yamawaki, Jing Gao, Kae Harada, Hiroshi Takeuchi, Masato Hirata, Takashi Kanematsu
The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into PI(3,4,5)P3 and the subsequent PI(3,4,5)P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5)P2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28659327/phosphoinositide-dependent-enrichment-of-actin-monomers-in-dendritic-spines-regulates-synapse-development-and-plasticity
#3
Wenliang Lei, Kenneth R Myers, Yanfang Rui, Siarhei Hladyshau, Denis Tsygankov, James Q Zheng
Dendritic spines are small postsynaptic compartments of excitatory synapses in the vertebrate brain that are modified during learning, aging, and neurological disorders. The formation and modification of dendritic spines depend on rapid assembly and dynamic remodeling of the actin cytoskeleton in this highly compartmentalized space, but the precise mechanisms remain to be fully elucidated. In this study, we report that spatiotemporal enrichment of actin monomers (G-actin) in dendritic spines regulates spine development and plasticity...
August 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28650469/a-compartmentalized-phosphoinositide-signaling-axis-at-cilia-is-regulated-by-inpp5e-to-maintain-cilia-and-promote-sonic-hedgehog-medulloblastoma
#4
S E Conduit, V Ramaswamy, M Remke, D N Watkins, B J Wainwright, M D Taylor, C A Mitchell, J M Dyson
Sonic Hedgehog (SHH) signaling at primary cilia drives the proliferation and progression of a subset of medulloblastomas, the most common malignant paediatric brain tumor. Severe side effects associated with conventional treatments and resistance to targeted therapies has led to the need for new strategies. SHH signaling is dependent on primary cilia for signal transduction suggesting the potential for cilia destabilizing mechanisms as a therapeutic target. INPP5E is an inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and more potently, the phosphoinositide (PI) 3-kinase product PtdIns(3,4,5)P3...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28621027/aromatic-amino-acids-and-their-relevance-in-the-specificity-of-the-ph-domain
#5
Ja Morales, M Sobol, L C Rodriguez-Zapata, P Hozak, E Castano
Phosphoinositides are phosphatidylinositol derived, well known to be second messengers in various cell signaling pathways as well as in processes such as cell differentiation, cellular stress response, gene transcription, and chromatin remodeling. The pleckstrin homology domain of phospholipase C-delta 1 is responsible for recognizing and binding to PI(4,5)P2 and for this reason has been widely used to study this phosphoinositide as a biosensor when it is conjugated to a fluorescent tag. In this work, we modified the primary structure of pleckstrin homology domain by site-specific mutagenesis to change the specificity for phosphoinositides...
June 16, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28572395/mtorc1-activity-repression-by-late-endosomal-phosphatidylinositol-3-4-bisphosphate
#6
Andrea L Marat, Alexander Wallroth, Wen-Ting Lo, Rainer Müller, Giuseppe Danilo Norata, Marco Falasca, Carsten Schultz, Volker Haucke
Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], synthesized by class II PI3K β (PI3KC2β) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2β hyperactivated mTORC1...
June 2, 2017: Science
https://www.readbyqxmd.com/read/28480512/regulation-of-immune-cell-signaling-by-ship1-a-phosphatase-scaffold-protein-and-potential-therapeutic-target
#7
REVIEW
Samantha D Pauls, Aaron J Marshall
The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor-dependent function in regulating phosphoinositide 3-kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P3 ; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling...
May 7, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28409542/inhibitory-receptor-fc%C3%AE-riib-mediates-the-effects-of-igg-on-a-phagosome-acidification-and-a-sequential-dephosphorylation-system-comprising-ships-and-inpp4a
#8
Tomohiro Segawa, Kaoru Hazeki, Kiyomi Nigorikawa, Atsuko Nukuda, Tomoki Tanizawa, Kenshiro Miyamoto, Shin Morioka, Osamu Hazeki
The relative abundance of phosphoinositide (PI) species on the phagosome membrane fluctuates over the course of phagocytosis. PtdIns(3,4,5)P3 and PtdIns(3,4)P2 rapidly increase in the forming of the phagocytic cup, following which they disappear after sealing of the cup. In the present study, we monitored the clearance of these PI species using the enhanced green fluorescent protein-fused pleckstrin homology domain of Akt, a fluorescence probe that binds both PtdIns(3,4,5)P3 and PtdIns(3,4)P2 in Raw 264.7 macrophages...
May 2017: Innate Immunity
https://www.readbyqxmd.com/read/28287133/activated-full-length-myosin-x-moves-processively-on-filopodia-with-large-steps-toward-diverse-two-dimensional-directions
#9
Osamu Sato, Hyun Suk Jung, Satoshi Komatsu, Yoshikazu Tsukasaki, Tomonobu M Watanabe, Kazuaki Homma, Mitsuo Ikebe
Myosin-X, (Myo 10), is an unconventional myosin that transports the specific cargos to filopodial tips, and is associated with the mechanism underlying filopodia formation and extension. To clarify the innate motor characteristic, we studied the single molecule movement of a full-length myosin-X construct with leucine zipper at the C-terminal end of the tail (M10(Full)LZ) and the tail-truncated myosin-X without artificial dimerization motif (BAP-M10(1-979)HMM). M10(Full)LZ localizes at the tip of filopodia like myosin-X full-length (M10(Full))...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28247205/the-mechanism-of-jurkat-cells-apoptosis-induced-by-aggregatibacter-actinomycetemcomitans-cytolethal-distending-toxin
#10
Hui-Ping Chen, Lu Li, Xu Chen, Mi-Fang Yang, Yu Ye, Xiao-Qian Wang, Yan Xu
Cytolethal distending toxin (CDT) which is produced by Aggregatibacter actinomycetemcomitans causes apoptosis in lymphocytes. But the specific mechanism is not clear. The aim of our research was to investigate the effect and mechanism during this process. The wild-type CdtA, CdtB, CdtC (CdtA(W), CdtB(W), CdtC(W)) and mutant CdtB (CdtB(M)) were expressed and purified respectively and the purity of each subunit was examined by BandScan software. And the type I deoxyribonuclease and PI-3,4,5-triphosphate (PI-3,4,5-P3, PIP3) phosphatase activity were detected by DNA agarose gel electrophoresis and enzyme-linked immunosorbent assay respectively...
June 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28157504/pi-3-4-5-p3-engagement-restricts-akt-activity-to-cellular-membranes
#11
Michael Ebner, Iva Lučić, Thomas A Leonard, Ivan Yudushkin
Protein kinase B/Akt regulates cellular metabolism, survival, and proliferation in response to hormones and growth factors. Hyperactivation of Akt is frequently observed in cancer, while Akt inactivation is associated with severe diabetes. Here, we investigated the molecular and cellular mechanisms that maintain Akt activity proportional to the activating stimulus. We show that binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3) or PI(3,4)P2 to the PH domain allosterically activates Akt by promoting high-affinity substrate binding...
February 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28130450/small-gtpase-rab8a-recruited-phosphatidylinositol-3-kinase-%C3%AE-regulates-signaling-and-cytokine-outputs-from-endosomal-toll-like-receptors
#12
Adam A Wall, Lin Luo, Yu Hung, Samuel J Tong, Nicholas D Condon, Antje Blumenthal, Matthew J Sweet, Jennifer L Stow
LPS-mediated activation of Toll-like receptor 4 (TLR4) in macrophages results in the coordinated release of proinflammatory cytokines, followed by regulatory mediators, to ensure that this potentially destructive pathway is tightly regulated. We showed previously that Rab8a recruits PI3Kγ for Akt-dependent signaling during TLR4 activation to limit the production of the proinflammatory cytokines IL-6 and IL-12p40 while enhancing the release of the regulatory/anti-inflammatory cytokine IL-10. Here we broaden the array of immune receptors controlled by Rab8a-PI3Kγ and further define the Rab-mediated membrane domains required for signaling...
March 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28105255/pi3k-ship2-pten-pathway-in-cell-polarity-and-hepatitis-c-virus-pathogenesis
#13
REVIEW
Aline Awad, Ama Gassama-Diagne
Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases...
January 8, 2017: World Journal of Hepatology
https://www.readbyqxmd.com/read/27999175/trans-inhibition-of-activation-and-proliferation-signals-by-fc-receptors-in-mast-cells-and-basophils
#14
Odile Malbec, Lydie Cassard, Marcello Albanesi, Friederike Jönsson, David Mancardi, Gaëtan Chicanne, Bernard Payrastre, Patrice Dubreuil, Eric Vivier, Marc Daëron
Allergic and autoimmune inflammation are associated with the activation of mast cells and basophils by antibodies against allergens or auto-antigens, respectively. Both cell types express several receptors for the Fc portion of antibodies, the engagement of which by antigen-antibody complexes controls their responses. When aggregated on the plasma membrane, high-affinity immunoglobulin E (IgE) receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA in mice, FcγRIIA in humans) induce these cells to release and secrete proinflammatory mediators, chemokines, and cytokines that account for clinical symptoms...
December 20, 2016: Science Signaling
https://www.readbyqxmd.com/read/27998989/inpp5e-regulates-phosphoinositide-dependent-cilia-transition-zone-function
#15
Jennifer M Dyson, Sarah E Conduit, Sandra J Feeney, Sandra Hakim, Tia DiTommaso, Alex J Fulcher, Absorn Sriratana, Georg Ramm, Kristy A Horan, Rajendra Gurung, Carol Wicking, Ian Smyth, Christina A Mitchell
Human ciliopathies, including Joubert syndrome (JBTS), arise from cilia dysfunction. The inositol polyphosphate 5-phosphatase INPP5E localizes to cilia and is mutated in JBTS. Murine Inpp5e ablation is embryonically lethal and recapitulates JBTS, including neural tube defects and polydactyly; however, the underlying defects in cilia signaling and the function of INPP5E at cilia are still emerging. We report Inpp5e(-/-) embryos exhibit aberrant Hedgehog-dependent patterning with reduced Hedgehog signaling. Using mouse genetics, we show increasing Hedgehog signaling via Smoothened M2 expression rescues some Inpp5e(-/-) ciliopathy phenotypes and "normalizes" Hedgehog signaling...
January 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/27903653/the-phosphatidylinositol-3-4-5-trisphosphate-pi-3-4-5-p3-binder-rasa3-regulates-phosphoinositide-3-kinase-pi3k-dependent-integrin-%C3%AE-iib%C3%AE-3-outside-in-signaling
#16
Anthony M Battram, Tom N Durrant, Ejaife O Agbani, Kate J Heesom, David S Paul, Raymond Piatt, Alastair W Poole, Peter J Cullen, Wolfgang Bergmeier, Samantha F Moore, Ingeborg Hers
The class I PI3K family of lipid kinases plays an important role in integrin αIIbβ3 function, thereby supporting thrombus growth and consolidation. Here, we identify Ras/Rap1GAP Rasa3 (GAP1(IP4BP)) as a major phosphatidylinositol 3,4,5-trisphosphate-binding protein in human platelets and a key regulator of integrin αIIbβ3 outside-in signaling. We demonstrate that cytosolic Rasa3 translocates to the plasma membrane in a PI3K-dependent manner upon activation of human platelets. Expression of wild-type Rasa3 in integrin αIIbβ3-expressing CHO cells blocked Rap1 activity and integrin αIIbβ3-mediated spreading on fibrinogen...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27897158/iqgap1-makes-pi-3-k-signalling-as-easy-as-pip-pip2-pip3
#17
Lucia E Rameh, Ashley M Mackey
Despite being one of the most studied signalling pathways, precisely how phospholipid synthesis is regulated in the phosphoinositide signalling cascade remains unclear. The scaffold protein IQGAP1 is now shown to orchestrate the assembly of a multi-enzyme complex that streamlines PtdIns(3,4,5)P3 synthesis to facilitate Akt activation in response to extracellular stimuli.
November 29, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27872186/the-interplay-between-calmodulin-and-membrane-interactions-with-the-pleckstrin-homology-domain-of-akt
#18
Constance Agamasu, Ruba H Ghanam, Fei Xu, Yong Sun, Yabing Chen, Jamil S Saad
The Akt protein, a serine/threonine kinase, plays important roles in cell survival, apoptosis, and oncogenes. Akt is translocated to the plasma membrane for activation. Akt-membrane binding is mediated by direct interactions between its pleckstrin homology domain (PHD) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). It has been shown that Akt activation in breast cancer cells is modulated by calmodulin (CaM). However, the molecular mechanism of the interplay between CaM and membrane binding is not established...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27870828/agonist-stimulated-phosphatidylinositol-3-4-5-trisphosphate-generation-by-scaffolded-phosphoinositide-kinases
#19
Suyong Choi, Andrew C Hedman, Samar Sayedyahossein, Narendra Thapa, David B Sacks, Richard A Anderson
Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P3 generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIIIα and PIPKIα, which sequentially generate PtdIns(3,4,5)P3 from phosphatidylinositol...
December 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27819060/the-hidden-conundrum-of-phosphoinositide-signaling-in-cancer
#20
Narendra Thapa, Xiaojun Tan, Suyong Choi, Paul F Lambert, Alan C Rapraeger, Richard A Anderson
Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P3 from PI(4,5)P2 and the subsequent activation of Akt and its downstream signaling cascades (e.g. mTORC1) dominates the landscape of phosphoinositide signaling axis in cancer research. However, PI(4,5)P2 is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC), and is now an established lipid messenger pivotal for different cellular events in cancer. Here, we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P2 and its generating enzymes, the phosphatidylinositol phosphate (PIP) kinases (PIPKs)...
July 2016: Trends in Cancer
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