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The Par3 polarity protein is an exocyst receptor essential for mammary cell survival.
Ahmed SM, Macara IG
(2017) Nat Commun 8: 14867
MeSH Terms: Animals, Apoptosis, Cadherins, Cell Adhesion Molecules, Cell Line, Cell Polarity, Cell Survival, Enzyme Activation, Epithelial Cells, Female, Gene Knockdown Techniques, Golgi Apparatus, Humans, Lysine, Mammary Glands, Animal, Models, Biological, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphorylation, Protein Domains, Proto-Oncogene Proteins c-akt, Vesicular Transport Proteins, rab GTP-Binding Proteins
Show Abstract · Added April 26, 2017
The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane-protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long-sought exocyst receptor required for targeted membrane-protein delivery.
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23 MeSH Terms
IQGAP1 makes PI(3)K signalling as easy as PIP, PIP, PIP.
Rameh LE, Mackey AM
(2016) Nat Cell Biol 18: 1263-1265
MeSH Terms: Animals, Humans, Models, Biological, Neoplasms, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, Signal Transduction, ras GTPase-Activating Proteins
Show Abstract · Added November 26, 2018
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)P synthesis to facilitate Akt activation in response to extracellular stimuli.
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MeSH Terms
VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
Nickols HH, Yuh JP, Gregory KJ, Morrison RD, Bates BS, Stauffer SR, Emmitte KA, Bubser M, Peng W, Nedelcovych MT, Thompson A, Lv X, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, Jones CK, Conn PJ
(2016) J Pharmacol Exp Ther 356: 123-36
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Astrocytes, Behavior, Animal, Brain, Dose-Response Relationship, Drug, Drug Discovery, GABA Agonists, HEK293 Cells, Humans, Inositol Phosphates, MAP Kinase Signaling System, Membrane Potentials, Mice, Mice, Inbred C57BL, Picolinic Acids, Pyridines, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Synaptic Transmission
Show Abstract · Added February 18, 2016
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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22 MeSH Terms
PI(3,5)P2 controls endosomal branched actin dynamics by regulating cortactin-actin interactions.
Hong NH, Qi A, Weaver AM
(2015) J Cell Biol 210: 753-69
MeSH Terms: Actin-Related Protein 2-3 Complex, Actins, Binding Sites, Cell Line, Tumor, Cortactin, Endosomes, Enzyme Activation, HeLa Cells, Humans, Phosphatidylinositol Phosphates, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Wiskott-Aldrich Syndrome Protein, Neuronal, rab GTP-Binding Proteins
Show Abstract · Added February 15, 2016
Branched actin critically contributes to membrane trafficking by regulating membrane curvature, dynamics, fission, and transport. However, how actin dynamics are controlled at membranes is poorly understood. Here, we identify the branched actin regulator cortactin as a direct binding partner of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and demonstrate that their interaction promotes turnover of late endosomal actin. In vitro biochemical studies indicated that cortactin binds PI(3,5)P2 via its actin filament-binding region. Furthermore, PI(3,5)P2 competed with actin filaments for binding to cortactin, thereby antagonizing cortactin activity. These findings suggest that PI(3,5)P2 formation on endosomes may remove cortactin from endosome-associated branched actin. Indeed, inhibition of PI(3,5)P2 production led to cortactin accumulation and actin stabilization on Rab7(+) endosomes. Conversely, inhibition of Arp2/3 complex activity greatly reduced cortactin localization to late endosomes. Knockdown of cortactin reversed PI(3,5)P2-inhibitor-induced actin accumulation and stabilization on endosomes. These data suggest a model in which PI(3,5)P2 binding removes cortactin from late endosomal branched actin networks and thereby promotes net actin turnover.
© 2015 Hong et al.
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16 MeSH Terms
An excitable compass guides chemotaxis?
Holmes WR
(2014) Biophys J 106: 989-90
MeSH Terms: Chemotaxis, Dictyostelium, Phosphatidylinositol Phosphates, Signal Transduction
Added February 26, 2016
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4 MeSH Terms
CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
Sobolik T, Su YJ, Wells S, Ayers GD, Cook RS, Richmond A
(2014) Mol Biol Cell 25: 566-82
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, HEK293 Cells, HL-60 Cells, Humans, Lymph Nodes, MAP Kinase Signaling System, MCF-7 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphatidylinositol Phosphates, Receptors, CXCR4, Receptors, Interleukin-8B, Signal Transduction, Up-Regulation
Show Abstract · Added March 14, 2014
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.
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25 MeSH Terms
Targeting Plasmodium PI(4)K to eliminate malaria.
McNamara CW, Lee MC, Lim CS, Lim SH, Roland J, Simon O, Yeung BK, Chatterjee AK, McCormack SL, Manary MJ, Zeeman AM, Dechering KJ, Kumar TS, Henrich PP, Gagaring K, Ibanez M, Kato N, Kuhen KL, Fischli C, Nagle A, Rottmann M, Plouffe DM, Bursulaya B, Meister S, Rameh L, Trappe J, Haasen D, Timmerman M, Sauerwein RW, Suwanarusk R, Russell B, Renia L, Nosten F, Tully DC, Kocken CH, Glynne RJ, Bodenreider C, Fidock DA, Diagana TT, Winzeler EA
(2013) Nature 504: 248-253
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Adenosine Triphosphate, Animals, Binding Sites, Cytokinesis, Drug Resistance, Fatty Acids, Female, Hepatocytes, Humans, Imidazoles, Life Cycle Stages, Macaca mulatta, Malaria, Male, Models, Biological, Models, Molecular, Phosphatidylinositol Phosphates, Plasmodium, Pyrazoles, Quinoxalines, Reproducibility of Results, Schizonts, rab GTP-Binding Proteins
Show Abstract · Added December 10, 2018
Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
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MeSH Terms
Auto-inhibition of Drs2p, a yeast phospholipid flippase, by its carboxyl-terminal tail.
Zhou X, Sebastian TT, Graham TR
(2013) J Biol Chem 288: 31807-15
MeSH Terms: Biological Transport, Active, Calcium-Transporting ATPases, Golgi Apparatus, Phosphatidylinositol Phosphates, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added January 20, 2015
Drs2p, a yeast type IV P-type ATPase (P4-ATPase), or flippase, couples ATP hydrolysis to phosphatidylserine translocation and the establishment of membrane asymmetry. A previous study has shown that affinity-purified Drs2p, possessing an N-terminal tandem affinity purification tag (TAPN-Drs2), retains ATPase and translocase activity, but Drs2p purified using a C-terminal tag (Drs2-TAPC) was inactive. In this study, we show that the ATPase activity of N-terminally purified Drs2p associates primarily with a proteolyzed form of Drs2p lacking the C-terminal cytosolic tail. Truncation of most of the Drs2p C-terminal tail sequence activates its ATPase activity by ∼4-fold. These observations are consistent with the hypothesis that the C-terminal tail of Drs2p is auto-inhibitory to Drs2p activity. Phosphatidylinositol 4-phosphate (PI(4)P) has been shown to positively regulate Drs2p activity in isolated Golgi membranes through interaction with the C-terminal tail. In proteoliposomes reconstituted with purified, N-terminally TAP-tagged Drs2p, both ATPase and flippase activity were significantly higher in the presence of PI(4)P. In contrast, PI(4)P had no significant effect on the activity of a truncated form of Drs2p, which lacked the C-terminal tail. This work provides the first direct evidence, in a purified system, that a phospholipid flippase is subject to auto-inhibition by its C-terminal tail, which can be relieved by a phosphoinositide to stimulate flippase activity.
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7 MeSH Terms
Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling.
McGuire VA, Gray A, Monk CE, Santos SG, Lee K, Aubareda A, Crowe J, Ronkina N, Schwermann J, Batty IH, Leslie NR, Dean JL, O'Keefe SJ, Boothby M, Gaestel M, Arthur JS
(2013) Mol Cell Biol 33: 4152-65
MeSH Terms: Animals, Cell Line, Enzyme Activation, Heat-Shock Proteins, Imidazoles, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinase 14, Neoplasm Proteins, Phosphatidylinositol Phosphates, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyridazines, Pyridines, Pyrimidines, Receptor Cross-Talk, Signal Transduction, Toll-Like Receptors
Show Abstract · Added March 7, 2014
The stimulation of Toll-like receptors (TLRs) on macrophages by pathogen-associated molecular patterns (PAMPs) results in the activation of intracellular signaling pathways that are required for initiating a host immune response. Both phosphatidylinositol 3-kinase (PI3K)-Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways are activated rapidly in response to TLR activation and are required to coordinate effective host responses to pathogen invasion. In this study, we analyzed the role of the p38-dependent kinases MK2/3 in the activation of Akt and show that lipopolysaccharide (LPS)-induced phosphorylation of Akt on Thr308 and Ser473 requires p38α and MK2/3. In cells treated with p38 inhibitors or an MK2/3 inhibitor, phosphorylation of Akt on Ser473 and Thr308 is reduced and Akt activity is inhibited. Furthermore, BMDMs deficient in MK2/3 display greatly reduced phosphorylation of Ser473 and Thr308 following TLR stimulation. However, MK2/3 do not directly phosphorylate Akt in macrophages but act upstream of PDK1 and mTORC2 to regulate Akt phosphorylation. Akt is recruited to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the membrane, where it is activated by PDK1 and mTORC2. Analysis of lipid levels in MK2/3-deficient bone marrow-derived macrophages (BMDMs) revealed a role for MK2/3 in regulating Akt activity by affecting availability of PIP3 at the membrane. These data describe a novel role for p38α-MK2/3 in regulating TLR-induced Akt activation in macrophages.
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24 MeSH Terms
Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is an AMPK target participating in contraction-stimulated glucose uptake in skeletal muscle.
Liu Y, Lai YC, Hill EV, Tyteca D, Carpentier S, Ingvaldsen A, Vertommen D, Lantier L, Foretz M, Dequiedt F, Courtoy PJ, Erneux C, Viollet B, Shepherd PR, Tavaré JM, Jensen J, Rider MH
(2013) Biochem J 455: 195-206
MeSH Terms: AMP-Activated Protein Kinases, Aminoimidazole Carboxamide, Animals, Cell Line, Glucose, Glucose Transporter Type 4, Humans, Insulin, Male, Muscle Contraction, Muscle, Skeletal, Opossums, Phosphatidylinositol 3-Kinase, Phosphatidylinositol Phosphates, Phosphorylation, Rats, Rats, Wistar
Show Abstract · Added April 17, 2014
PIKfyve (FYVE domain-containing phosphatidylinositol 3-phosphate 5-kinase), the lipid kinase that phosphorylates PtdIns3P to PtdIns(3,5)P2, has been implicated in insulin-stimulated glucose uptake. We investigated whether PIKfyve could also be involved in contraction/AMPK (AMP-activated protein kinase)-stimulated glucose uptake in skeletal muscle. Incubation of rat epitrochlearis muscles with YM201636, a selective PIKfyve inhibitor, reduced contraction- and AICAriboside (5-amino-4-imidazolecarboxamide riboside)-stimulated glucose uptake. Consistently, PIKfyve knockdown in C2C12 myotubes reduced AICAriboside-stimulated glucose transport. Furthermore, muscle contraction increased PtdIns(3,5)P2 levels and PIKfyve phosphorylation. AMPK phosphorylated PIKfyve at Ser307 both in vitro and in intact cells. Following subcellular fractionation, PIKfyve recovery in a crude intracellular membrane fraction was increased in contracting versus resting muscles. Also in opossum kidney cells, wild-type, but not S307A mutant, PIKfyve was recruited to endosomal vesicles in response to AMPK activation. We propose that PIKfyve activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. PIKfyve is a new AMPK substrate whose phosphorylation at Ser307 could promote PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation.
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17 MeSH Terms