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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/28174296/ncs1-regulates-ca2-dependent-focal-exocytosis-of-golgi-derived-vesicles-to-help-phagocytic-uptake-in-macrophages
#2
Nimi Vashi, Syed Bilal Ahmad Andrabi, Swapnil Ghanwat, Mrutyunjay Suar, Dhiraj Kumar
During phagocytic uptake by macrophages, role of Golgi apparatus was previously ruled out. Notably all such reports were limited to Fcγ-receptor mediated phagocytosis. Here we unravel a highly devolved mechanism for recruitment of Golgi-derived secretory vesicles during phagosome biogenesis, which was important for uptake of most cargos except IgG-coated ones. We report recruitment of Mannosidase-II positive Golgi-derived vesicles during uptake of diverse targets including latex beads, E. coli, Salmonella Typhimurium and Mycobacterium tuberculosis in human and mouse macrophages...
February 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28157504/pi-3-4-5-p3-engagement-restricts-akt-activity-to-cellular-membranes
#3
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/28136018/co-existence-of-ras-activation-in-a-chemotactic-signal-transduction-pathway-and-in-an-autonomous-wave-forming-system
#4
Mary Ecke, Günther Gerisch
The activation of Ras is common to two activities in cells of Dictyostelium discoideum: the directed movement in a gradient of chemoattractant and the autonomous generation of propagating waves of actin polymerization on the substrate-attached cell surface. We produced large cells by electric-pulse induced fusion to simultaneously study both activities in one cell. For imaging, a fluorescent label for activated Ras was combined with labels for filamentous actin, PIP3, or PTEN. Chemotactic responses were elicited in a diffusion gradient of cyclic AMP...
January 31, 2017: Small GTPases
https://www.readbyqxmd.com/read/28119806/class-i-phosphatidylinositol-3-kinase-inhibitors-for-cancer-therapy
#5
REVIEW
Wennan Zhao, Yuling Qiu, Dexin Kong
The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors...
January 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/28106075/phosphatidylinositol-3-4-bisphosphate-regulates-neurite-initiation-and-dendrite-morphogenesis-via-actin-aggregation
#6
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/28063949/vitamin-d-supplementation-inhibits-oxidative-stress-and-upregulate-sirt1-ampk-glut4-cascade-in-high-glucose-treated-3t3l1-adipocytes-and-in-adipose-tissue-of-high-fat-diet-fed-diabetic-mice
#7
Prasenjit Manna, Arunkumar E Achari, Sushil K Jain
This study examined the hypothesis that vitamin-D prevents oxidative stress and upregulates glucose metabolism via activating insulin-independent signaling molecules in 3T3-L1 adipocytes and in high fat diet (HFD)-fed mice. To investigate the mechanism 3T3L1 adipocytes were treated with high glucose (HG, 25 mM) and 1,25(OH)2D3 (1,25-dihydroxyvitamin D3) (0-50 nM). Results showed that 1,25(OH)2D3 supplementation decreased NOX4 expression, ROS production, NF-κB phosphorylation, and increased the expression of Nrf2 and Trx in HG-treated cells...
January 4, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28018608/digenic-mutations-of-human-ocrl-paralogs-in-dent-s-disease-type-2-associated-with-chiari-i-malformation
#8
Daniel Duran, Sheng Chih Jin, Tyrone DeSpenza, Carol Nelson-Williams, Andrea G Cogal, Elizabeth W Abrash, Peter C Harris, John C Lieske, Serena Je Shimshak, Shrikant Mane, Kaya Bilguvar, Michael L DiLuna, Murat Günel, Richard P Lifton, Kristopher T Kahle
OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression...
2016: Human Genome Variation
https://www.readbyqxmd.com/read/28003865/skin-aging-dependent-activation-of-the-pi3k-signaling-pathway-via-downregulation-of-pten-increases-intracellular-ros-in-human-dermal-fibroblasts
#9
Eun-Mi Noh, Jinny Park, Hwa-Ryung Song, Jeong-Mi Kim, Minok Lee, Hyun-Kyung Song, On-Yu Hong, Pyoung H Whang, Myung-Kwan Han, Kang-Beom Kwon, Jong-Suk Kim, Young-Rae Lee
Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway...
2016: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/27960076/a-plasma-membrane-template-for-macropinocytic-cups
#10
Douwe M Veltman, Thomas D Williams, Gareth Bloomfield, Bi-Chang Chen, Eric Betzig, Robert H Insall, Robert R Kay
Macropinocytosis is a fundamental mechanism that allows cells to take up extracellular liquid into large vesicles. It critically depends on the formation of a ring of protrusive actin beneath the plasma membrane, which develops into the macropinocytic cup. We show that macropinocytic cups in Dictyostelium are organised around coincident intense patches of PIP3, active Ras and active Rac. These signalling patches are invariably associated with a ring of active SCAR/WAVE at their periphery, as are all examined structures based on PIP3 patches, including phagocytic cups and basal waves...
December 13, 2016: ELife
https://www.readbyqxmd.com/read/27933776/regulation-of-a-coupled-marcks-pi3k-lipid-kinase-circuit-by-calmodulin-single-molecule-analysis-of-a-membrane-bound-signaling-module
#11
Brian P Ziemba, G Hayden Swisher, Glenn Masson, John E Burke, Roger L Williams, Joseph J Falke
Amoeboid cells that employ chemotaxis to travel up an attractant gradient possess a signaling network assembled on the leading edge of the plasma membrane that senses the gradient and remodels the actin mesh and cell membrane to drive movement in the appropriate direction. In leukocytes such as macrophages and neutrophils, and perhaps in other amoeboid cells as well, the leading edge network includes a positive feedback loop in which the signaling of multiple pathway components is cooperatively coupled. Cytoplasmic Ca(2+) is a recently recognized component of the feedback loop at the leading edge where it stimulates phosphoinositide-3-kinase (PI3K) and the production of its product signaling lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3)...
November 22, 2016: Biochemistry
https://www.readbyqxmd.com/read/27919433/sodc-modulates-ras-and-pkb-signaling-in-dictyostelium
#12
Boris Castillo, Seon-Hee Kim, Mujataba Sharief, Tong Sun, Lou W Kim
We have previously reported that the basal RasG activity is aberrantly high in cells lacking Superoxide dismutase C (SodC). Here we report that other Ras proteins such as RasC and RasD activities are not affected in sodC(-) cells and mutagenesis studies showed that the presence of the Cys(118) in the Ras proteins is essential for the superoxide-mediated activation of Ras proteins in Dictyostelium. In addition to the loss of SodC, lack of extracellular magnesium ions increased the level of intracellular superoxide and active RasG proteins...
January 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/27902465/gene-and-microrna-modulation-upon-trabectedin-treatment-in-a-human-intrahepatic-cholangiocarcinoma-paired-patient-derived-xenograft-and-cell-line
#13
Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes...
27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27897158/iqgap1-makes-pi-3-k-signalling-as-easy-as-pip-pip2-pip3
#14
Lucia E Rameh, Ashley M Mackey
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)P3 synthesis to facilitate Akt activation in response to extracellular stimuli.
November 29, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27896420/level-of-agreement-between-three-dimensional-volumetric-ultrasound-and-real-time-conventional-ultrasound-in-the-assessment-of-synovitis-tenosynovitis-and-erosions-in-rheumatoid-arthritis-patients
#15
Carlos Acebes, Neil McKay, Anna Ciechomska, Nicola Alcorn, John P Harvie, Barbara Robson, Nico Groenendijk, Moira McDonald, Alison Wilson, Jesus Garrido
The aim of the study was to assess agreement between three-dimensional volumetric ultrasound (3D US) performed by inexperienced staff and real-time conventional ultrasound (2D US) performed by experienced rheumatologists in detecting and scoring rheumatoid arthritis (RA) lesions. Thirty-one RA patients underwent examination of seven joints by 2D and 3D US for synovitis and tenosynovitis in B and PD modes and erosions in B mode. A global score for synovitis and global counts for synovitis, tenosynovitis and erosions were also calculated for every patient...
February 2017: Rheumatology International
https://www.readbyqxmd.com/read/27872195/estrogen-receptors-and-signaling-in-fibroids-role-in-pathobiology-and-therapeutic-implications
#16
Mostafa A Borahay, Mehmet R Asoglu, Aymara Mas, Sarah Adam, Gokhan S Kilic, Ayman Al-Hendy
Uterine fibroids are the most common gynecologic tumors with a significant medical and financial burden. Several genetic, hormonal, and biological factors have been shown to contribute to the development and growth of fibroid tumors. Of these factors, estrogen is particularly critical since fibroids are considered estrogen dependent because no prepubertal cases have been described in the literature and tumors tend to regress after menopause. Understanding the role of estrogen in fibroids is not only important for understanding the pathobiology of fibroids but also for the development of successful therapeutics...
November 20, 2016: Reproductive Sciences
https://www.readbyqxmd.com/read/27852846/a-transformation-defective-polyomavirus-middle-t-antigen-with-a-novel-defect-in-pi3-kinase-signaling
#17
Deborah Denis, Cecile Rouleau, Brian S Schaffhausen
: Middle T antigen (MT), the principal oncoprotein of murine polyomavirus, transforms by association with cellular proteins. Protein phosphatase 2A (PP2A), YAP, Src family tyrosine kinases, Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1 (PLCγ1) have all been implicated in MT transformation. Mutant dl1015, with deletion of residues 338 to 347 in the C-terminal region, has been an enigma, because the basis for its transformation defect has not been apparent. This work probes the dl1015 region of MT...
January 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27799542/cilia-have-high-camp-levels-that-are-inhibited-by-sonic-hedgehog-regulated-calcium-dynamics
#18
Bryn S Moore, Ann N Stepanchick, Paul H Tewson, Cassandra M Hartle, Jin Zhang, Anne Marie Quinn, Thomas E Hughes, Tooraj Mirshahi
Protein kinase A (PKA) phosphorylates Gli proteins, acting as a negative regulator of the Hedgehog pathway. PKA was recently detected within the cilium, and PKA activity specifically in cilia regulates Gli processing. Using a cilia-targeted genetically encoded sensor, we found significant basal PKA activity. Using another targeted sensor, we measured basal ciliary cAMP that is fivefold higher than whole-cell cAMP. The elevated basal ciliary cAMP level is a result of adenylyl cyclase 5 and 6 activity that depends on ciliary phosphatidylinositol (3,4,5)-trisphosphate (PIP3), not stimulatory G protein (Gαs), signaling...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27666481/phosphatidylinositol-3-4-5-trisphosphate-binds-to-sortilin-and-competes-with-neurotensin-implications-for-very-low-density-lipoprotein-binding
#19
Robert P Sparks, Jermaine L Jenkins, Gregory E Miner, Yan Wang, Wayne C Guida, Charles E Sparks, Rutilio A Fratti, Janet D Sparks
Sortilin is a multi-ligand sorting receptor that interacts with B100-containing VLDL and LDL as well as other ligands including neurotensin (NT). The current study investigates the hypothesis that phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generated downstream of insulin action can directly bind to sortilin. NT binds to sortilin at a well characterized site via its carboxy terminus (C-term). Using a crystal structure of human sortilin (hsortilin), PIP3 is predicted to bind at this C-term site. Binding of PIP3 to hsortilin is demonstrated using surface plasmon resonance (SPR) flowing PIP3 nanodiscs over immobilized hsortilin...
October 21, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27606721/differential-receptor-dependencies-expression-and-significance-of-muscarinic-m1-receptors-in-the-biology-of-prostate-cancer
#20
Abdul Mannan Baig, Naveed A Khan, Vardah Effendi, Zohaib Rana, H R Ahmad, Farhat Abbas
Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer...
January 2017: Anti-cancer Drugs
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