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pi(3,4)p2

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https://www.readbyqxmd.com/read/28196852/inpp4b-and-pten-loss-leads-to-pi-3-4-p2-accumulation-and-inhibition-of-pi3k-in-tnbc
#1
Darien E Reed, Kevan M Shokat
: Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR) and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients and still lacks an effective targeted therapy(1,2). Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer(3). Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3,4-bisphosphate (PI-3,4-P2) creating phosphatidylinositol-3-phosphate(4)...
February 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28157504/pi-3-4-5-p3-engagement-restricts-akt-activity-to-cellular-membranes
#2
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/28138522/the-activation-loop-of-pip5k-functions-as-a-membrane-sensor-essential-for-lipid-substrate-processing
#3
Aizhuo Liu, Dexin Sui, Dianqing Wu, Jian Hu
Phosphatidylinositol 4-phosphate 5-kinase (PIP5K), a representative member of the phosphatidylinositol phosphate kinase (PIPK) family, is a major enzyme that biosynthesizes the signaling molecule PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) in eukaryotic cells. The stringent specificity toward lipid substrates and the high sensitivity to the membrane environment strongly suggest a membrane-sensing mechanism, but the underlying structural basis is still largely unknown. We present a nuclear magnetic resonance (NMR) study on a peptide commensurate with a PIP5K's activation loop, which has been reported to be a determinant of lipid substrate specificity and subcellular localization of PIP5K...
November 2016: Science Advances
https://www.readbyqxmd.com/read/28130450/rab8a-recruited-pi3k%C3%AE-regulates-signaling-and-cytokine-outputs-from-endosomal-toll-like-receptors
#4
Adam A Wall, Lin Luo, Yu Hung, Samuel J Tong, Nicholas D Condon, Antje Blumenthal, Matthew J Sweet, Jennifer L Stow
Lipopolysaccharide (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 previously showed that Rab8a recruits PI3Kγ for Akt-dependent signaling during TLR4 activation to limit the production of the pro-inflammatory cytokines IL-6 and IL-12p40, while enhancing the release of the regulatory/anti-inflammatory cytokine IL-10...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28106075/phosphatidylinositol-3-4-bisphosphate-regulates-neurite-initiation-and-dendrite-morphogenesis-via-actin-aggregation
#5
Shu-Xin Zhang, Li-Hui Duan, Shun-Ji He, Gui-Feng Zhuang, Xiang Yu
Neurite initiation is critical for neuronal morphogenesis and early neural circuit development. Recent studies showed that local actin aggregation underneath the cell membrane determined the site of neurite initiation. An immediately arising question is what signaling mechanism initiated actin aggregation. Here we demonstrate that local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis...
January 20, 2017: Cell Research
https://www.readbyqxmd.com/read/28105255/pi3k-ship2-pten-pathway-in-cell-polarity-and-hepatitis-c-virus-pathogenesis
#6
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/28035047/the-acyltransferase-lycat-controls-specific-phosphoinositides-and-related-membrane-traffic
#7
Leslie N Bone, Roya M Dayam, Minhyoung Lee, Nozomu Kono, Gregory D Fairn, Hiroyuki Arai, Roberto J Botelho, Costin N Antonescu
Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains poorly understood. We examined the role of the PI acyltransferase LYCAT in control of PIPs and PIP-dependent membrane traffic. LYCAT silencing selectively perturbed the levels and localization of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol-3-phosphate and the membrane traffic dependent on these specific PIPs but was without effect on phosphatidylinositol-4-phosphate or biosynthetic membrane traffic...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28017365/acclimation-to-salt-modifies-the-activation-of-several-osmotic-stress-activated-lipid-signalling-pathways-in-chlamydomonas
#8
Harold J G Meijer, John A J van Himbergen, Alan Musgrave, Teun Munnik
Osmotic stress rapidly activates several phospholipid signalling pathways in the unicellular alga Chlamydomonas. In this report, we have studied the effects of salt-acclimation on growth and phospholipid signalling. Growing cells on media containing 100 mM NaCl increased their salt-tolerance but did not affect the overall phospholipid content, except that levels of phosphatidylinositol phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] were reduced by one-third. When these NaCl-acclimated cells were treated with increasing concentrations of salt, the same lipid signalling pathways as in non-acclimated cells were activated...
March 2017: Phytochemistry
https://www.readbyqxmd.com/read/27998989/inpp5e-regulates-phosphoinositide-dependent-cilia-transition-zone-function
#9
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/27910774/comparison-of-the-chemical-composition-and-bioactive-components-of-fruiting-bodies-and-submerged-cultured-mycelia-of-the-willow-bracket-medicinal-mushroom-phellinus-igniarius-agaricomycetes
#10
Huawei Zeng, Wenfeng Wang, Menghua Ma, Guohua Xu, Mei Ying-Jie, Jianfan Sund
Chemical compositions and bioactive ingredients of dried fruiting bodies from Phellinus igniarius (CGMCC no. 50095) (P1) and submerged culture of Ph. igniarius dried mycelia (P2) were investigated in this study. It was found that glutamic acid was regarded as a major amino acid in P1 (1.20%) and was approximately 2.55-fold higher than that in P2 (0.47%). Total amino acids in P1 (5.36%) were slightly higher than in P2 (4.09%). The amounts of iron, zinc, copper, and manganese in P1 were 1.96-3.42 times as high as those in P2, whereas potassium, sodium, and magnesium in P2 were almost 2...
2016: International Journal of Medicinal Mushrooms
https://www.readbyqxmd.com/read/27870828/agonist-stimulated-phosphatidylinositol-3-4-5-trisphosphate-generation-by-scaffolded-phosphoinositide-kinases
#11
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...
November 21, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27859053/b-cell-intrinsic-function-of-tapp-adaptors-in-controlling-germinal-center-responses-and-autoantibody-production-in-mice
#12
Nipun Jayachandran, Ivan Landego, Sen Hou, Dario R Alessi, Aaron J Marshall
Control of B-cell signal transduction is critical to prevent production of pathological autoantibodies. Tandem PH domain containing proteins (TAPPs) specifically bind PI(3,4)P2, a phosphoinositide product generated by PI 3-kinases and the phosphatase SHIP. TAPP KI mice bearing PH domain-inactivating mutations in both TAPP1 and TAPP2 genes, uncoupling them from PI(3,4)P2, exhibit increased BCR-induced activation of the kinase Akt and develop lupus-like characteristics including anti-DNA antibodies and deposition of immune complexes in kidneys...
November 15, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27819060/the-hidden-conundrum-of-phosphoinositide-signaling-in-cancer
#13
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
https://www.readbyqxmd.com/read/27716613/lipid-phosphatase-ship2-functions-as-oncogene-in-colorectal-cancer-by-regulating-pkb-activation
#14
Elmer Hoekstra, Asha M Das, Marcella Willemsen, Marloes Swets, Peter J K Kuppen, Christien J van der Woude, Marco J Bruno, Jigisha P Shah, Timo L M Ten Hagen, John D Chisholm, William G Kerr, Maikel P Peppelenbosch, Gwenny M Fuhler
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene...
September 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27698019/ralf-mediated-activation-of-arf6-controls-rickettsia-typhi-invasion-by-co-opting-phosphoinositol-metabolism
#15
Kristen E Rennoll-Bankert, M Sayeedur Rahman, Mark L Guillotte, Stephanie S Lehman, Magda Beier-Sexton, Joseph J Gillespie, Abdu F Azad
Rickettsiae are obligate intracellular pathogens that induce their uptake into nonphagocytic cells; however, the events instigating this process are incompletely understood. Importantly, diverse Rickettsia species are predicted to utilize divergent mechanisms to colonize host cells, as nearly all adhesins and effectors involved in host cell entry are differentially encoded in diverse Rickettsia species. One particular effector, RalF, a Sec7 domain-containing protein that functions as a guanine nucleotide exchange factor of ADP-ribosylation factors (Arfs), is critical for Rickettsia typhi (typhus group rickettsiae) entry but pseudogenized or absent from spotted fever group rickettsiae...
December 2016: Infection and Immunity
https://www.readbyqxmd.com/read/27601656/in-b-cells-phosphatidylinositol-5-phosphate-4-kinase-%C3%AE-synthesizes-pi-4-5-p2-to-impact-mtorc2-and-akt-signaling
#16
Simon J Bulley, Alaa Droubi, Jonathan H Clarke, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Robin F Irvine
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27417116/arf6-and-the-5-phosphatase-of-synaptojanin-1-regulate-autophagy-in-cone-photoreceptors
#17
Ashley A George, Sara Hayden, Gail R Stanton, Susan E Brockerhoff
Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1-deficient zebrafish mutant, nrc(a14) . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development...
July 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/27401686/the-joubert-syndrome-protein-inpp5e-controls-ciliogenesis-by-regulating-phosphoinositides-at-the-apical-membrane
#18
Wenyan Xu, Miaomiao Jin, Ruikun Hu, Hong Wang, Fan Zhang, Shiaulou Yuan, Ying Cao
Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PtdIns), are tightly regulated both temporally and spatially by PtdIns phosphatases and kinases. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause Joubert syndrome, a human disorder associated with numerous ciliopathic defects, including renal cyst formation, linking phosphoinositides to ciliopathies. However, the molecular mechanism by which INPP5E-mediated PtdIns signaling regulates ciliogenesis and cystogenesis is unclear...
January 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27292112/biallelic-mutations-of-vac14-in-pediatric-onset-neurological-disease
#19
Guy M Lenk, Krystyna Szymanska, Grazyna Debska-Vielhaber, Malgorzata Rydzanicz, Anna Walczak, Monika Bekiesinska-Figatowska, Stefan Vielhaber, Kerstin Hallmann, Piotr Stawinski, Sonja Buehring, David A Hsu, Wolfram S Kunz, Miriam H Meisler, Rafal Ploski
In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI...
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27283411/inhibition-of-trek-2-k-channels-by-pi-4-5-p2-an-intrinsic-mode-of-regulation-by-intracellular-atp-via-phosphatidylinositol-kinase
#20
Joohan Woo, Dong Hoon Shin, Hyun Jong Kim, Hae Young Yoo, Yin-Hua Zhang, Joo Hyun Nam, Woo Kyung Kim, Sung Joon Kim
TWIK-related two-pore domain K(+) channels 1 and 2 (TREKs) are activated under various physicochemical conditions. However, the directions in which they are regulated by PI(4,5)P2 and intracellular ATP are not clearly presented yet. In this study, we investigated the effects of ATP and PI(4,5)P2 on overexpressed TREKs (HEK293T and COS-7) and endogenously expressed TREK-2 (mouse astrocytes and WEHI-231 B cells). In all of these cells, both TREK-1 and TREK-2 currents were spontaneously increased by dialysis with ATP-free pipette solution for whole-cell recording (ITREK-1,w-c and ITREK-2w-c) or by membrane excision for inside-out patch clamping without ATP (ITREK-1,i-o and ITREK-2,i-o)...
August 2016: Pflügers Archiv: European Journal of Physiology
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