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pi(3,4)p2

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https://www.readbyqxmd.com/read/29884706/tapp-adaptors-control-b-cell-metabolism-by-modulating-the-phosphatidylinositol-3-kinase-signaling-pathway-a-novel-regulatory-circuit-preventing-autoimmunity
#1
Nipun Jayachandran, Edgard M Mejia, Kimia Sheikholeslami, Affan A Sher, Sen Hou, Grant M Hatch, Aaron J Marshall
Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity...
June 8, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29874576/schwann-cell-specific-deletion-of-phosphatidylinositol-4-kinase-alpha-causes-aberrant-myelination
#2
Alejandro Alvarez-Prats, Ivana Bjelobaba, Zane Aldworth, Takashi Baba, Daniel Abebe, Yeun Ju Kim, Stanko S Stojilkovic, Mark Stopfer, Tamas Balla
Active membrane remodeling during myelination relies on phospholipid synthesis and membrane polarization, both of which are known to depend on inositol phospholipids. Here, we show that sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions. Surprisingly, prolonged inhibition of PI4KA in immortalized mouse SCs failed to decrease plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) levels or PI 3-kinase (PI3K) activation, in spite of large reductions in plasma membrane PI4P levels...
June 5, 2018: Cell Reports
https://www.readbyqxmd.com/read/29695412/dimerization-of-the-voltage-sensing-phosphatase-controls-its-voltage-sensing-and-catalytic-activity
#3
Vamseedhar Rayaprolu, Perrine Royal, Karen Stengel, Guillaume Sandoz, Susy C Kohout
Multimerization is a key characteristic of most voltage-sensing proteins. The main exception was thought to be the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP). In this study, we show that multimerization is also critical for Ci-VSP function. Using coimmunoprecipitation and single-molecule pull-down, we find that Ci-VSP stoichiometry is flexible. It exists as both monomers and dimers, with dimers favored at higher concentrations. We show strong dimerization via the voltage-sensing domain (VSD) and weak dimerization via the phosphatase domain...
April 25, 2018: Journal of General Physiology
https://www.readbyqxmd.com/read/29470948/direct-analysis-of-pi-3-4-5-p-3-using-liquid-chromatography-electrospray-ionization-tandem-mass-spectrometry
#4
Hai H Bui, Phillip E Sanders, Diane Bodenmiller, Ming Shang Kuo, Gregory P Donoho, Anthony S Fischl
Phosphatidylinositol (3,4,5) trisphosphate (PIP3 ) is a biologically active membrane phospholipid that is essential for the growth and survival of all eukaryotic cells. We describe a new method that directly measures PIP3 and describe the HPLC separation and measurement of the positional isomers of phosphatidylinositol bisphosphate, PI(3,5)P2 , PI(3,4)P2 and PI(4,5)P2 . Mass spectrometric analyses were performed online using ultra-high performance liquid chromatography (UHPLC)-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative multiple-reaction monitoring (MRM) modes...
April 15, 2018: Analytical Biochemistry
https://www.readbyqxmd.com/read/29469807/gram-domain-proteins-specialize-functionally-distinct-er-pm-contact-sites-in-human-cells
#5
Marina Besprozvannaya, Eamonn Dickson, Hao Li, Kenneth S Ginburg, Donald M Bers, Johan Auwerx, Jodi Nunnari
Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human family members, GRAMD1a and GRAMD2a, demonstrates that they are ER-PM MCS proteins, which mark separate regions of the plasma membrane (PM) and perform distinct functions in vivo. GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at ER-PM contacts in a PIP lipid-dependent manner and pre-marks the subset of PI(4,5)P2-enriched ER-PM MCSs utilized for STIM1 recruitment...
February 22, 2018: ELife
https://www.readbyqxmd.com/read/29447222/kinetics-of-pten-mediated-pi-3-4-5-p3-hydrolysis-on-solid-supported-membranes
#6
Chun Liu, Sanghamitra Deb, Vinicius S Ferreira, Eric Xu, Tobias Baumgart
Phosphatidylinositides play important roles in cellular signaling and migration. Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) is an important phosphatidylinositide because it acts as a secondary messenger to trigger cell movement and proliferation. A high level of PI(3,4,5)P3 at the plasma membrane is known to contribute to tumorigenesis. One key enzyme that regulates PI(3,4,5)P3 levels at the plasma membrane is phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which dephosphorylates PI(3,4,5)P3 through hydrolysis to form phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2)...
2018: PloS One
https://www.readbyqxmd.com/read/29425097/molecular-mechanism-for-inhibition-of-twinfilin-by-phosphoinositides
#7
Markku Hakala, Maria Kalimeri, Giray Enkavi, Ilpo Vattulainen, Pekka Lappalainen
Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity...
March 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29359392/importance-of-phosphoinositide-binding-by-human-%C3%AE-defensin-3-for-akt-dependent-cytokine-induction
#8
Thanh Kha Phan, Fung T Lay, Mark D Hulett
Host defense peptides (HDPs) are well-characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β-defensin 3 (HBD-3) belongs to a well-known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co-stimulatory marker expression. HBD-3-stimulated cytokine induction is NF-κB-dependent and was initially suggested to act via G protein-coupled C-C chemokine receptor phospholipase C (PLC) and/or Toll-like receptor signaling...
January 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29343273/inpp4b-promotes-cell-survival-via-sgk3-activation-in-npm1-mutated-leukemia
#9
Hongjun Jin, Liyuan Yang, Lu Wang, Zailin Yang, Qian Zhan, Yao Tao, Qin Zou, Yuting Tang, Jingrong Xian, Shuaishuai Zhang, Yipei Jing, Ling Zhang
BACKGROUND: Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML...
January 17, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29320679/effect-of-h-bond-donor-lipids-on-phosphatidylinositol-3-4-5-trisphosphate-ionization-and-clustering
#10
Zachary T Graber, Joseph Thomas, Emily Johnson, Arne Gericke, Edgar E Kooijman
The phosphoinositide, phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3 ), is a key signaling lipid in the inner leaflet of the cell plasma membrane, regulating diverse signaling pathways including cell growth and migration. In this study we investigate the impact of the hydrogen-bond donor lipids phosphatidylethanolamine (PE) and phosphatidylinositol (PI) on the charge and phase behavior of PI(3,4,5)P3 . PE and PI can interact with PI(3,4,5)P3 through hydrogen-bond formation, leading to altered ionization behavior and charge distribution within the PI(3,4,5)P3 headgroup...
January 9, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29229838/architecture-of-the-human-pi4kiii%C3%AE-lipid-kinase-complex
#11
Joshua A Lees, Yixiao Zhang, Michael S Oh, Curtis M Schauder, Xiaoling Yu, Jeremy M Baskin, Kerry Dobbs, Luigi D Notarangelo, Pietro De Camilli, Thomas Walz, Karin M Reinisch
Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell's interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI) to PI4P, the precursor of PI(4,5)P2 and PI(3,4,5)P3 This conversion is catalyzed by the PI4KIIIα complex, comprising a lipid kinase, PI4KIIIα, and two regulatory subunits, TTC7 and FAM126. We here report the structure of this complex at 3...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29161595/a-coincidence-detection-mechanism-controls-px-bar-domain-mediated-endocytic-membrane-remodeling-via-an-allosteric-structural-switch
#12
Wen-Ting Lo, Andreja Vujičić Žagar, Fabian Gerth, Martin Lehmann, Dymtro Puchkov, Oxana Krylova, Christian Freund, Leonardo Scapozza, Oscar Vadas, Volker Haucke
Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2 ) at endocytic sites...
November 20, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29103771/the-down-regulation-of-tapp2-inhibits-the-migration-of-esophageal-squamous-cell-carcinoma-and-predicts-favorable-outcome
#13
Fang Liu, Fei Ye, Zongyu Guan, Yi Zhou, Fengjun Ji, Qing Zhang, Jianping Zhang, Tianyi Zhang, Songhua Lu
Tandem pH domain-containing proteins TAPP1 and TAPP2 are adaptor proteins that specifically bind to phosphatidylinositol-3,4-bisphosphate, or PI(3,4)P2, a product of phosphoinositide 3-kinases (PI3K). Although PI3K enzymes have multiple functions in cell biology, including cell migration, the functions of PI (3, 4) P2 and its binding proteins are not well understood. Previously studies found that TAPP2 is highly expressed in primary leukemic B cells that have strong migratory capacity. However, the function and underlying mechanisms of TAPP2 in ESCC remain largely unknown...
September 12, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29100049/pip-ing-lipids-on-membranes-pten-takes-the-cake
#14
Archna Ravi, Brooke M Emerling
In this issue of Molecular Cell, Malek et al. (2017) describe a novel HPLC-MS method permitting separation of PI(3,4)P2 and PI(4,5)P2 , a technical issue hindering the phosphoinositide signaling field. They use this method to uncover a new target and critical role for PTEN in cancer.
November 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29078297/increased-intracellular-ca-2-concentrations-prevent-membrane-localization-of-ph-domains-through-the-formation-of-ca-2-phosphoinositides
#15
Jin Ku Kang, Ok-Hee Kim, June Hur, So Hee Yu, Santosh Lamichhane, Jin Wook Lee, Uttam Ojha, Jeong Hee Hong, Cheol Soon Lee, Ji-Young Cha, Young Jae Lee, Seung-Soon Im, Young Joo Park, Cheol Soo Choi, Dae Ho Lee, In-Kyu Lee, Byung-Chul Oh
Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca2+ concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca2+ homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca2+ acts as a negative regulator of insulin signaling. Chronic intracellular Ca2+ overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29057313/a-lipid-off-switch-for-mtorc1
#16
Alexander Wallroth, Volker Haucke
Mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of metabolism, cell growth and survival. Our finding that local phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2 ] synthesis at late endosomes/ lysosomes by class II PI3Kβ (PI3KC2β) represses mTORC1 identifies PI3KC2β as a pharmacological target for the treatment of diabetes and cancer.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29056325/pten-regulates-pi-3-4-p-2-signaling-downstream-of-class-i-pi3k
#17
Mouhannad Malek, Anna Kielkowska, Tamara Chessa, Karen E Anderson, David Barneda, Pınar Pir, Hiroki Nakanishi, Satoshi Eguchi, Atsushi Koizumi, Junko Sasaki, Véronique Juvin, Vladimir Y Kiselev, Izabella Niewczas, Alexander Gray, Alexandre Valayer, Dominik Spensberger, Marine Imbert, Sergio Felisbino, Tomonori Habuchi, Soren Beinke, Sabina Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan Clark, Phillip T Hawkins, Len R Stephens
The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3 . PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2 . The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2 , which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells...
November 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29020973/the-%C3%AE-melanocyte-stimulating-hormone-peroxisome-proliferator-activated-receptor-%C3%AE-pathway-down-regulates-proliferation-in-melanoma-cell-lines
#18
Enrica Flori, Eleonora Rosati, Giorgia Cardinali, Daniela Kovacs, Barbara Bellei, Mauro Picardo, Vittoria Maresca
BACKGROUND: The α-Melanocyte Stimulating Hormone (αMSH)/Melanocortin-1 receptor (MC1R) interaction promotes melanogenesis through the cAMP/PKA pathway. The direct induction of this pathway by Forskolin (FSK) is also known to enhance melanocyte proliferation. αMSH acts as a mitogenic agent in melanocytes and its effect on proliferation of melanoma cells is less known. We previously identified the αMSH/Peroxisome Proliferator Activated Receptor (PPARγ) pathway as a new pathway on the B16-F10 mouse melanoma cell line...
October 11, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28990469/identification-and-characterization-of-novel-genes-expressed-preferentially-in-the-corpora-allata-or-corpora-cardiaca-during-the-juvenile-hormone-synthetic-period-in-the-silkworm-bombyx-mori
#19
Syusaku Taguchi, Masafumi Iwami, Taketoshi Kiya
Juvenile hormone (JH) plays important roles in insect development and physiology. JH titer is tightly regulated to coordinately adjust systemic physiology and development. Although control of JH titer is explained by the expression of JH biosynthetic enzymes in the corpora allata (CA), molecular mechanisms that regulate the expression of these genes remain elusive. In the present study, to identify novel regulators of JH biosynthetic genes, we conducted a gene expression screen using the CA and corpora cardiaca (CC) of the silkworm, Bombyx mori, in the JH synthesis period...
October 2017: Zoological Science
https://www.readbyqxmd.com/read/28961003/membrane-order-is-a-key-regulator-of-divalent-cation-induced-clustering-of-pi-3-5-p2-and-pi-4-5-p2
#20
Maria J Sarmento, Ana Coutinho, Aleksander Fedorov, Manuel Prieto, Fábio Fernandes
Although the evidence for the presence of functionally important nanosized phosphorylated phosphoinositide (PIP)-rich domains within cellular membranes has accumulated, very limited information is available regarding the structural determinants for compartmentalization of these phospholipids. Here, we used a combination of fluorescence spectroscopy and microscopy techniques to characterize differences in divalent cation-induced clustering of PI(4,5)P2 and PI(3,5)P2. Through these methodologies we were able to detect differences in divalent cation-induced clustering efficiency and cluster size...
October 13, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
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