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Stephen W Roth, Moshe D Bitterman, Morris J Birnbaum, Michelle L Bland
In obese adipose tissue, Toll-like receptor signaling in macrophages leads to insulin resistance in adipocytes. Similarly, Toll signaling in the Drosophila larval fat body blocks insulin-dependent growth and nutrient storage. We find that Toll acts cell autonomously to block growth but not PI(3,4,5)P3 production in fat body cells expressing constitutively active PI3K. Fat body Toll signaling blocks whole-animal growth in rictor mutants lacking TORC2 activity, but not in larvae lacking Pdk1. Phosphorylation of Akt on the Pdk1 site, Thr342, is significantly reduced by Toll signaling, and expression of mutant AktT342D rescues cell and animal growth, nutrient storage, and viability in animals with active Toll signaling...
March 6, 2018: Cell Reports
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
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, which 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 carboxy-terminal tail-region, while the two ADF/cofilin like ADF-H domains of twinfilin bind phosphoinositides only with low affinity...
February 7, 2018: Journal of Biological Chemistry
Rafael Pulido
The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing...
January 30, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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
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
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
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
Gergő Gulyás, Glória Radvánszki, Rita Matuska, András Balla, László Hunyady, Tamas Balla, Péter Várnai
Plasma membrane (PM) localization of Ras proteins is crucial for transmitting signals upon mitogen stimulation. Post-translational lipid modification of Ras proteins plays an important role in their recruitment to the PM. Electrostatic interactions between negatively charged PM phospholipids and basic amino acids found in K-Ras4B (K-Ras) but not in H-Ras are important for permanent K-Ras localization to the PM. Here, we investigated how acute depletion of negatively charged PM polyphosphoinositides (PPIns) from the PM alters the intracellular distribution and activity of K- and H-Ras proteins...
November 17, 2017: Journal of Biological Chemistry
Ana Raquel Ramos, William's Elong Edimo, Christophe Erneux
Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes...
September 5, 2017: Advances in Biological Regulation
Somadri Ghosh, Céline Huber, Quentin Siour, Sérgio B Sousa, Michael Wright, Valérie Cormier-Daire, Christophe Erneux
The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown...
September 4, 2017: Human Mutation
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
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
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
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...
October 26, 2017: Oncogene
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
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
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...
June 2017: European Journal of Immunology
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
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
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