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Cellular Signalling

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https://www.readbyqxmd.com/read/28716664/advances-and-challenges-in-the-search-for-d2-and-d3-dopamine-receptor-selective-compounds
#1
REVIEW
Amy E Moritz, R Benjamin Free, David R Sibley
Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the D2R and D3R subtypes are highly homologous, creating compounds with sufficient subtype-selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing D2R- or D3R-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions...
July 14, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28711719/g-protein-coupled-receptor-kinases-past-present-and-future
#2
REVIEW
Konstantin E Komolov, Jeffrey L Benovic
This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction...
July 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28711718/phospholipase-d1-is-a-regulator-of-platelet-mediated-inflammation
#3
Meike Klier, Nina Sarah Gowert, Sven Jäckel, Christoph Reinhardt, Margitta Elvers
Glycoprotein (GP)Ib is not only required for stable thrombus formation but for platelet-mediated inflammatory responses. Phospholipase (PL)D1 is essential for GPIb-dependent aggregate formation under high shear conditions while nothing is known about PLD1-induced regulation of GPIb in platelet-mediated inflammation and the underlying mechanisms. This study aimed to investigate the relevance of PLD1 for platelet-mediated endothelial and leukocyte recruitment and activation in vitro and in vivo. Pld1(-/-) platelets showed strongly reduced adhesion to TNFα stimulated endothelial cells (ECs) under high shear conditions ex vivo...
July 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28711717/phosphatidylinositol-4-phosphate-5-kinase-%C3%AE-contributes-to-toll-like-receptor-2-mediated-immune-responses-in-microglial-cells-stimulated-with-lipoteichoic-acid
#4
Tu Thi Ngoc Nguyen, Eunjeong Seo, Juyong Choi, Oanh Thi Tu Le, Ji Yun Kim, Ilo Jou, Sang Yoon Lee
Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important lipid regulator of membrane signaling and remodeling processes. Accumulating evidence indicates a link between PIP2 metabolism and Toll-like receptor (TLR) signaling, a key transducer of immune responses such as inflammation, phagocytosis, and autophagy. Microglia are immune effector cells that serve as macrophages in the brain. Here, we examined the potential role of phosphatidylinositol 4-phosphate 5-kinase α (PIP5Kα), a PIP2-producing enzyme, in TLR2 signaling in microglial cells...
July 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28711716/impact-of-paroxetine-on-proximal-%C3%AE-adrenergic-receptor-signaling
#5
Shuchi Guo, Rhonda L Carter, Laurel A Grisanti, Walter J Koch, Douglas G Tilley
β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances βAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial βAR expression in mouse models of heart failure...
July 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28709644/horizontal-transfer-of-mir-106a-b-from-cisplatin-resistant-hepatocarcinoma-cells-can-alter-the-sensitivity-of-cervical-cancer-cells-to-cisplatin
#6
Grace R Raji, T V Sruthi, Lincy Edatt, K Haritha, S Sharath Shankar, V B Sameer Kumar
Recent studies indicate that horizontal transfer of genetic material can act as a communication tool between heterogenous populations of tumour cells, thus altering the chemosensitivity of tumour cells. The present study was designed to check whether the horizontal transfer of miRNAs released by cisplatin resistant (Cp-r) Hepatocarcinoma cells can alter the sensitivity of cervical cancer cells. For this exosomes secreted by cisplatin resistant and cisplatin sensitive HepG2 cells (EXres and EXsen) were isolated and characterised...
July 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28709643/hypoxia-induced-suppression-of-c-myc-by-hif-2%C3%AE-in-human-pulmonary-endothelial-cells-attenuates-tfam-expression
#7
Ali J Zarrabi, Derrick Kao, Dustin T Nguyen, Joseph Loscalzo, Diane E Handy
The adaptive response to hypoxia is mediated in large part by stabilization of the hypoxia-inducible factors, HIF-1α and HIF-2α. A hallmark of this response is the metabolic shift to decreased oxidative phosphorylation and increased glycolysis. We hypothesized that hypoxic responses would include a suppression of mitochondrial gene expression. We determined the effects of hypoxia on TFAM, a key mitochondrial transcription factor, in normal pulmonary artery endothelial cells. Hypoxia decreased gene expression of TFAM and that of its upstream regulator, the transcriptional co-activator PGC1β...
July 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28697999/the-protective-role-of-tet2-in-erythroid-iron-homeostasis-against-oxidative-stress-and-erythropoiesis
#8
Shanqi Guo, Xingkang Jiang, Yuanyuan Wang, Liwei Chen, Huzi Li, Xiaojiang Li, Yingjie Jia
Although previous studies suggested that stress erythropoiesis and iron metabolism regulate each other to increase iron availability for hemoglobin synthesis, the molecular bases determining its different traits remain elusive. In addition, global DNA demethylation has been reported during mouse erythropoiesis in vivo. However, the understanding of iron-related genes through DNA demethylation under stress erythropoiesis is largely unknown. In the current study, we found disordered iron homeostasis and misregulated hepcidin-ferroportin axis under stress erythropoiesis...
July 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28694028/the-pivotal-role-of-extracellular-signal-regulated-kinase-in-gap-junction-mediated-regulation-of-txnip
#9
Shan Gao, Xiling Zhang, Kun Gao, Zhen Zhang, Yanru Huang, Ryuichi Yoda, Jian Yao
Gap junctions (GJs) play a major role in the control of cell structure, function, and metabolism. However, the molecular mechanisms involved are still poorly understood. Given that thioredoxin-interacting protein (TXNIP) regulates a broad range of cellular processes, we tested the possible involvement of TXNIP. Disruption of GJs with several chemical GJ inhibitors or connexin43 (Cx43) siRNA potently suppressed TXNIP, which was preceded by an activation of extracellular signal-regulated kinase (ERK). Inhibition of ERK or its upstream kinase with chemical inhibitors prevented the reduction of TXNIP...
July 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28687494/sphingolipid-abnormalities-in-cancer-multidrug-resistance-chicken-or-egg
#10
Wing-Kee Lee, Richard N Kolesnick
The cancer multidrug resistance (MDR) phenotype encompasses a myriad of molecular, genetic and cellular alterations resulting from progressive oncogenic transformation and selection. Drug efflux transporters, in particular the MDR P-glycoprotein ABCB1, play an important role in MDR but cannot confer the complete phenotype alone indicating parallel alterations are prerequisite. Sphingolipids are essential constituents of lipid raft domains and directly participate in functionalization of transmembrane proteins, including providing an optimal lipid microenvironment for multidrug transporters, and are also perturbed in cancer...
July 4, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28669827/mitochondria-elongation-is-mediated-through-sirt1-mediated-mfn1-stabilization
#11
Nguyen Thi Kim Oanh, Yong-Yea Park, Hyeseong Cho
Mitochondria are highly dynamic organelles that change size and morphology by fusing together or dividing through fission. In response to cellular cues, signaling cascades may post-translationally modify mitochondria-shaping proteins, which lead to a change in mitochondria morphology. Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability...
June 29, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28668722/the-tyrosine-y250-2-39-in-frizzled-4-defines-a-conserved-motif-important-for-structural-integrity-of-the-receptor-and-recruitment-of-disheveled
#12
Katerina Strakova, Pierre Matricon, Chika Yokota, Elisa Arthofer, Ondrej Bernatik, David Rodriguez, Ernest Arenas, Jens Carlsson, Vitezslav Bryja, Gunnar Schulte
Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y250(2.39)) in the intracellular loop 1 (IL1) of human FZD4. We have found Y250(2...
June 29, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28668721/pde2-at-the-crossway-between-camp-and-cgmp-signalling-in-the-heart
#13
REVIEW
Silvio Weber, Miriam Zeller, Kaomei Guan, Frank Wunder, Michael Wagner, Ali El-Armouche
The cyclic nucleotides cAMP and cGMP are central second messengers in cardiac cells and critical regulators of cardiac physiology as well as pathophysiology. Consequently, subcellular compartmentalization allows for spatiotemporal control of cAMP/cGMP metabolism and subsequent regulation of their respective effector kinases PKA or PKG is most important for cardiac function in health and disease. While acute cAMP-mediated signalling is a mandatory prerequisite for the physiological fight-or-flight response, sustained activation of this pathway may lead to the progression of heart failure...
June 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28658604/smurf1-targets-securin-for-ubiquitin-dependent-degradation-and-regulates-the-metaphase-to-anaphase-transition
#14
Rongfei Wei, Baoliang Li, Jing Guo, Mengyuan Li, Ruimin Zhu, Xingjiu Yang, Ran Gao
The HECT E3 ligase Smurf1 (Smad ubiquitination regulatory factor 1) plays a critical role in several important biological pathways by targeting many proteins for ubiquitination and degradation, such as Smad1/5, MEKK2 and RhoA. However, the function of Smurf1 in metaphase-to-anaphase transition remains unclear. Here, we show that Smurf1 interacts with and targets Securin, an inhibitor of sister-chromatid separation, for poly-ubiquitination and proteasomal degradation. Further results demonstrate that Securin is a physiological substrate of Smurf1 in MEF cells...
June 27, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28652146/downregulation-of-pkc%C3%AE-pard3-pard6b-is-responsible-for-lung-adenocarcinoma-cell-emt-and-invasion
#15
Qiyuan Zhou, Jingbo Dai, Tianji Chen, Laura A Dada, Xu Zhang, Wei Zhang, Malcolm M DeCamp, Robert A Winn, Jacob I Sznajder, Guofei Zhou
Atypical protein kinase C ζ (PKCζ) forms an apico-basal polarity complex with Partitioning Defective (Pard) 3 and Pard6 to regulate normal epithelial cell apico-basolateral polarization. The dissociation of the PKCζ/Pard3/Pard6 complex is essential for the disassembly of the tight/adherens junction and epithelial-mesenchymal transition (EMT) that is critical for tumor spreading. Loss of cell polarity and epithelial organization is strongly correlated with malignancy and tumor progression in some other cancer types...
June 24, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28652145/diverse-structures-functions-and-uses-of-fk506-binding-proteins
#16
REVIEW
Julia Maeve Bonner, Gabrielle L Boulianne
FK506 (Tacrolimus), isolated from Streptomyces tsukubaenis is a powerful immunosuppressant shown to inhibit T cell activation. FK506 mediated immunosuppression requires the formation of a complex between FK506, a FK506 binding protein (FKBP) and calcineurin. Numerous FKBPs have been identified in a wide range of species, from single celled organisms to humans. FKBPs show peptidylprolyl cis/trans isomerase (PPIase) activity and have been shown to affect a wide range of cellular processes including protein folding, receptor signaling and apoptosis...
June 23, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28648944/tubulin-beta-3-and-4-are-involved-in-the-generation-of-early-fibrotic-stages
#17
Marta E Wawro, Katarzyna Sobierajska, Wojciech M Ciszewski, Waldemar Wagner, Marta Frontczak, Katarzyna Wieczorek, Jolanta Niewiarowska
The endothelial-mesenchymal transition (EndMT) is a fundamental cellular mechanism that occurs under both physiological and pathological conditions and includes the fibrotic stages of numerous organs, namely, the skin, kidneys, heart, lungs and liver. Endothelial cells that undergo EndMT are one of the main source of (myo)fibroblasts in fibrotic tissues. A critical step in cellular transdifferentiation is morphological change, which is engineered by the reorganization of cytoskeletal elements such as microtubules...
June 23, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28648945/phosphodiesterase-5-inhibition-as-a-therapeutic-target-for-ischemic-stroke-a-systematic-review-of-preclinical-studies
#18
Joakim N E Ölmestig, Ida R Marlet, Atticus H Hainsworth, Christina Kruuse
Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals...
June 22, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28647573/focal-adhesion-kinase-signaling-regulates-anti-inflammatory-function-of-bone-marrow-mesenchymal-stromal-cells-induced-by-biomechanical-force
#19
Hyun Jung Lee, Miguel F Diaz, Adesuwa Ewere, Scott D Olson, Charles S Cox, Pamela L Wenzel
Mesenchymal stromal cells (MSCs) have tremendous potential for use in regenerative medicine due to their multipotency and immune cell regulatory functions. Biomimetic physical forces have been shown to direct differentiation and maturation of MSCs in tissue engineering applications; however, the effect of force on immunomodulatory activity of MSCs has been largely overlooked. Here we show in human bone marrow-derived MSCs that wall shear stress (WSS) equivalent to the fluid frictional force present in the adult arterial vasculature significantly enhances expression of four genes that mediate MSC immune regulatory function, PTGS2, HMOX1, IL1RN, and TNFAIP6...
June 21, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28645565/from-the-outside-from-within-biological-and-therapeutic-relevance-of-signal-transduction-in-t-cell-acute-lymphoblastic-leukemia
#20
REVIEW
Mariana L Oliveira, Padma Akkapeddi, Isabel Alcobia, Afonso R Almeida, Bruno A Cardoso, Rita Fragoso, Teresa L Serafim, João T Barata
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell-intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development...
June 21, 2017: Cellular Signalling
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