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PI(4,5)P2

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https://www.readbyqxmd.com/read/29100049/pip-ing-lipids-on-membranes-pten-takes-the-cake
#1
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
#2
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 Lm, 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 Ca(2+) concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca(2+) homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca(2+) acts as a negative regulator of insulin signaling. Chronic intracellular Ca(2+) 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/29073094/mechanistic-principles-underlying-regulation-of-the-actin-cytoskeleton-by-phosphoinositides
#3
Yosuke Senju, Maria Kalimeri, Essi V Koskela, Pentti Somerharju, Hongxia Zhao, Ilpo Vattulainen, Pekka Lappalainen
The actin cytoskeleton powers membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Membrane phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], regulate the activities of many actin-binding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin, but the underlying molecular mechanisms have remained elusive. Moreover, because of a lack of available methodology, the dynamics of membrane interactions have not been experimentally determined for any ABP...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29068313/phosphatidylinositol-4-5-bisphosphate-optical-uncaging-potentiates-exocytosis
#4
Alexander M Walter, Rainer Müller, Bassam Tawfik, Keimpe Db Wierda, Paulo S Pinheiro, André Nadler, Anthony W McCarthy, Iwona Ziomkiewicz, Martin Kruse, Gregor Reither, Jens Rettig, Martin Lehmann, Volker Haucke, Bertil Hille, Carsten Schultz, Jakob Balslev Sorensen
Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] is essential for exocytosis. Classical ways of manipulating PI(4,5)P2 levels are slower than metabolism, making it difficult to distinguish effects of PI(4,5)P2 from those of its metabolites. We developed a membrane-permeant, photoactivatable PI(4,5)P2, which is loaded into cells in an inactive form and activated by light, allowing sub-second increases in PI(4,5)P2 levels. By combining this compound with electrophysiological measurements in mouse adrenal chromaffin cells, we show that PI(4,5)P2 uncaging potentiates exocytosis and identify synaptotagmin-1 (the Ca(2+) sensor for exocytosis) and Munc13-2 (a vesicle priming protein) as the relevant effector proteins...
October 25, 2017: ELife
https://www.readbyqxmd.com/read/29056325/pten-regulates-pi-3-4-p2-signaling-downstream-of-class-i-pi3k
#5
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
#6
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/28993456/phosphatidylinositol-4-5-bisphosphate-dependent-oligomerization-of-the-pseudomonas-aeruginosa-cytotoxin-exou
#7
Angelica Zhang, Jeffrey L Veesenmeyer, Alan R Hauser
The Pseudomonas aeruginosa type III secretion system delivers effector proteins directly into target cells, allowing the bacterium to modulate host cell functions. ExoU is the most cytotoxic of the known effector proteins and has been associated with more severe infections in humans. ExoU is a patatin-like A2 phospholipase requiring the cellular host factors phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and ubiquitin for its activation in vitro We demonstrated that PI(4,5)P2 also induces oligomerization of ExoU and that this PI(4,5)P2-mediated oligomerization does not require ubiquitin...
October 9, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28988317/identification-of-critical-amino-acids-in-the-proximal-c-terminal-of-trek-2-k-channel-for-activation-by-acidic-phi-and-atp-dependent-inhibition
#8
Joohan Woo, Young Keul Jun, Yin-Hua Zhang, Joo Hyun Nam, Dong Hoon Shin, Sung Joon Kim
TWIK-related two-pore domain K(+) channels (TREKs) are regulated by intracellular pH (pHi) and Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Previously, Glu(306) in proximal C-terminal (pCt) of mouse TREK-1 was identified as the pHi-sensing residue. The direction of PI(4,5)P2 sensitivity is controversial, and we have recently shown that TREKs are inhibited by intracellular ATP via endogenous PI(4,5)P2 formation. Here we investigate the anionic and cationic residues of pCt for the pHi and ATP-sensitivity in human TREK-2 (hTREK-2)...
October 8, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28970821/hpv8-e6-interferes-with-syntenin-2-expression-through-deregulation-of-differentiation-methylation-and-phosphatidylinositide-kinase-dependent-mechanisms
#9
Benjamin Marx, Daliborka Miller-Lazic, John Doorbar, Slawomir Majewski, Kay Hofmann, Martin Hufbauer, Baki Akgül
The E6 oncoproteins of high-risk human papillomaviruses (HPV) of genus alpha contain a short peptide sequence at the carboxy-terminus, the PDZ binding domain, with which they interact with the corresponding PDZ domain of cellular proteins. Interestingly, E6 proteins from papillomaviruses of genus beta (betaPV) do not encode a comparable PDZ binding domain. Irrespective of this fact, we previously showed that the E6 protein of HPV8 (betaPV type) could circumvent this deficit by targeting the PDZ protein Syntenin-2 through transcriptional repression (Lazic et al...
2017: Frontiers in Microbiology
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
#10
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
https://www.readbyqxmd.com/read/28954864/cortical-actin-contributes-to-spatial-organization-of-er-pm-junctions
#11
Ting-Sung Hsieh, Yu-Ju Chen, Chi-Lun Chang, Wan-Ru Lee, Jen Liou
ER-plasma membrane (PM) junctions mediate crucial activities ranging from Ca(2+) signaling to lipid metabolism. Spatial organization of ER-PM junctions may modulate the extent and location of these cellular activities. However, the morphology and distribution of ER-PM junctions are not well characterized. Using photoactivated localization microscopy (PALM), we reveal that the contact area of single ER-PM junctions is mainly oblong with the dimensions of ∼120 nm × ∼80 nm in HeLa cells. Using total internal reflection fluorescence microscopy (TIRFM) and structure illumination microscopy (SIM), we show that cortical actin contributes to spatial distribution and stability of ER-PM junctions...
September 27, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28941037/phosphatidylinositol-4-5-bisphosphate-targets-double-c2-domain-protein-b-to-the-plasma-membrane
#12
Lirin Michaeli, Irit Gottfried, Maria Bykhovskaia, Uri Ashery
Double C2 domain protein B (DOC2B) is a high-affinity Ca(2+) sensor that translocates from the cytosol to the plasma membrane (PM) and promotes vesicle priming and fusion. However, the molecular mechanism underlying its translocation and targeting to the PM in living cells is not completely understood. DOC2B interacts in vitro with the PM components phosphatidylserine, phosphatidylinositol (4, 5)-bisphosphate [PI(4, 5)P2 ] and target SNAREs (t-SNAREs). Here, we show that PI(4, 5)P2 hydrolysis at the PM of living cells abolishes DOC2B translocation, whereas manipulations of t-SNAREs and other phosphoinositides have no effect...
September 22, 2017: Traffic
https://www.readbyqxmd.com/read/28939768/plasma-membrane-phosphatidylinositol-4-phosphate-and-4-5-bisphosphate-determine-the-distribution-and-function-of-k-ras4b-but-not-h-ras-proteins
#13
Gergö 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. Posttranslational 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...
September 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28932942/required-hydrophobicity-of-fluorescent-reporters-for-phosphatidylinositol-family-of-lipid-enzymes
#14
Jarod Waybright, Weigang Huang, Angela Proctor, Xiaoyang Wang, Nancy L Allbritton, Qisheng Zhang
The phosphatidylinositol (PtdIns) family of lipids plays important roles in cell differentiation, proliferation, and migration. Abnormal expression, mutation, or regulation of their metabolic enzymes has been associated with various human diseases such as cancer, diabetes, and bipolar disorder. Recently, fluorescent derivatives have increasingly been used as chemical probes to monitor either lipid localization or enzymatic activity. However, the requirements of a good probe have not been well defined, particularly modifications on the diacylglycerol side chain partly due to challenges in generating PtdIns lipids...
November 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28923975/control-of-actin-polymerization-via-the-coincidence-of-phosphoinositides-and-high-membrane-curvature
#15
Frederic Daste, Astrid Walrant, Mikkel R Holst, Jonathan R Gadsby, Julia Mason, Ji-Eun Lee, Daniel Brook, Marcel Mettlen, Elin Larsson, Steven F Lee, Richard Lundmark, Jennifer L Gallop
The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42⋅guanosine triphosphate and SNX9 activate N-WASP-WIP- and Arp2/3-mediated actin nucleation...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28916189/phosphoinositide-5-phosphatase-activities-control-cell-motility-in-glioblastoma-two-phosphoinositides-pi-4-5-p2-and-pi-3-4-p2-are-involved
#16
REVIEW
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
https://www.readbyqxmd.com/read/28879546/the-btk-dependent-pip5k1%C3%AE-lipid-kinase-activation-by-fas-counteracts-fasl-induced-cell-death
#17
Aurélie Rossin, Nadia Lounnas, Jérôme Durivault, Giorgia Miloro, Laurent Gagnoux-Palacios, Anne-Odile Hueber
The Fas/FasL system plays a critical role in death by apoptosis and immune escape of cancer cells. The Fas receptor being ubiquitously expressed in tissues, its apoptotic-inducing function, initiated upon FasL binding, is tightly regulated by several negative regulatory mechanisms to prevent inappropriate cell death. One of them, involving the non-receptor tyrosine kinase Btk, was reported mainly in B cells and only poorly described. We report here that Btk negatively regulates, through its tyrosine kinase activity, the FasL-mediated cell death in epithelial cell lines from colon cancer origin...
September 6, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28871048/an-emerging-case-for-membrane-pore-formation-as-a-common-mechanism-for-the-unconventional-secretion-of-fgf2-and-il-1%C3%AE
#18
REVIEW
David Brough, Pablo Pelegrin, Walter Nickel
Extracellular proteins with important signalling roles in processes, such as inflammation and angiogenesis, are known to employ unconventional routes of protein secretion. Although mechanisms of unconventional protein secretion are beginning to emerge, the precise molecular details have remained elusive for the majority of cargo proteins secreted by unconventional means. Recent findings suggest that for two examples of unconventionally secreted proteins, interleukin 1β (IL-1β) and fibroblast growth factor 2 (FGF2), the common molecular principle of pore formation may be shared...
October 1, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28871046/loss-of-ocrl-increases-ciliary-pi-4-5-p2-in-oculocerebrorenal-syndrome-of-lowe
#19
Philipp P Prosseda, Na Luo, Biao Wang, Jorge A Alvarado, Yang Hu, Yang Sun
Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL1, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane poorly understood. Here we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P...
September 4, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28869677/fibroblasts-derived-from-patients-with-opsismodysplasia-display-ship2-specific-cell-migration-and-adhesion-defects
#20
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
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