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Advances in Biological Regulation

David L Ebenezer, Panfeng Fu, Vidyani Suryadevara, Yutong Zhao, Viswanathan Natarajan
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes...
September 29, 2016: Advances in Biological Regulation
Achim Löf, Jochen P Müller, Martin Benoit, Maria A Brehm
The large multimeric plasma glycoprotein von Willebrand factor (VWF) is essential for primary hemostasis by recruiting platelets to sites of vascular injury. VWF multimers respond to elevated hydrodynamic forces by elongation, thereby increasing their adhesiveness to platelets. Thus, the activation of VWF is force-induced, as is its inactivation. Due to these attributes, VWF is a highly interesting system from a biophysical point of view, and is well suited for investigation using biophysical approaches. Here, we give an overview on recent studies that predominantly employed biophysical methods to gain novel insights into multiple aspects of VWF: Electron microscopy was used to shed light on the domain structure of VWF and the mechanism of VWF secretion...
September 28, 2016: Advances in Biological Regulation
Guido Wabnitz, Emre Balta, Yvonne Samstag
T-cells need to be tightly regulated during their activation and effector phase to assure an appropriate defence against cancer or pathogens and - vice versa - to avoid autoimmune reactions. Regulatory signals are provided via the immune synapse between T-cells and antigen-presenting cells (APCs) or target cells. The stability and kinetics of immune synapse formation is critical for proper T-cell functions. It requires dynamic rearrangements of the actin cytoskeleton necessary for organized spatio-temporal redistribution of receptors and adhesion molecules...
September 27, 2016: Advances in Biological Regulation
Yoe-Sik Bae, Ha Young Lee, Young Su Jung, Mingyu Lee, Pann-Ghill Suh
Among the phospholipase C (PLC) isoforms, PLCγ not only has unique structural characteristics in terms of harboring SH2 and SH3 domains but also mediates growth factor-induced signaling pathways. PLCγ isoforms are expressed in several innate immune cell types, including macrophages, natural killer cells, mast cells, and neutrophils. Stimulation of Fc receptor or integrin in innate immune cells induces PLCγ activation, which leads to phosphoinositide hydrolysis and calcium increase. The products of PLCγ activity mediate the innate immune response by regulating respiratory burst, phagocytosis, cell adhesion, and cell migration...
September 27, 2016: Advances in Biological Regulation
Isabel Mérida, Pedro Torres-Ayuso, Antonia Ávila-Flores, Javier Arranz-Nicolás, Elena Andrada, María Tello-Lafoz, Rosa Liébana, Raquel Arcos
Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the activation of the PLCγ/Ras/ERK axis, providing a critical checkpoint to inhibit T cell responses. Upregulation of these isoforms limits Ras activation, leading to hypo-responsive, anergic states similar to those caused by tumors. Recent studies have identified DGKα upregulation in tumor lymphocyte infiltrates, and cells from DGKα and ζ deficient mice show enhanced antitumor activity, suggesting that limitation of DAG based signals by DGK is used by tumors to evade immune attack...
September 23, 2016: Advances in Biological Regulation
Daniel M Raben, Casey N Barber
Lipids play a vital role in the health and functioning of neurons and interest in the physiological role of neuronal lipids is certainly increasing. One neuronal function in which neuronal lipids appears to play key roles in neurotransmission. Our understanding of the role of lipids in the synaptic vesicle cycle and neurotransmitter release is becoming increasingly more important. Much of the initial research in this area has highlighted the major roles played by the phosphoinositides (PtdIns), diacylglycerol (DAG), and phosphatidic acid (PtdOH)...
September 20, 2016: Advances in Biological Regulation
Chandrika Gowda, Chunhua Song, Malika Kapadia, Jonathon L Payne, Tommy Hu, Yali Ding, Sinisa Dovat
The IKZF1 gene encodes the Ikaros protein, a zinc finger transcriptional factor that acts as a master regulator of hematopoiesis and a tumor suppressor in leukemia. Impaired activity of Ikaros is associated with the development of high-risk acute lymphoblastic leukemia (ALL) with a poor prognosis. The molecular mechanisms that regulate Ikaros' function as a tumor suppressor and regulator of cellular proliferation are not well understood. We demonstrated that Ikaros is a substrate for Casein Kinase II (CK2), an oncogenic kinase that is overexpressed in ALL...
September 18, 2016: Advances in Biological Regulation
Matthieu A Raess, Sylvie Friant, Belinda S Cowling, Jocelyn Laporte
Myotubularins define a large family of proteins conserved through evolution. Several members are mutated in different neuromuscular diseases including centronuclear myopathies and Charcot-Marie-Tooth (CMT) neuropathies, or are linked to a predisposition to obesity and cancer. While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P2 implicated in membrane trafficking and autophagy, and producing PtdIns5P, others lack key residues in the catalytic site and are classified as dead-phosphatases...
September 15, 2016: Advances in Biological Regulation
Carlo Cosimo Campa, Emilio Hirsch
Rab11 and phosphoinositides are signal transducers able to direct the delivery of membrane components to the cell surface. Rab11 is a small GTPase that, by cycling from an active to an inactive state, controls key events of vesicular transport, while phosphoinositides are major determinants of membrane identity, modulating compartmentalized small GTPase function. By sharing common effectors, these two signal transducers synergistically direct vesicular traffic to specific intracellular membranes. This review focuses on the latest advances regarding the mechanisms that ensure the compartmentalized regulation of Rab11 function through its interaction with phosphoinositides...
September 14, 2016: Advances in Biological Regulation
Andrea Pellagatti, Jacqueline Boultwood
Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS...
August 21, 2016: Advances in Biological Regulation
Karen E Anderson, Veronique Juvin, Jonathan Clark, Len R Stephens, Phillip T Hawkins
Phosphoinositides in primary mammalian tissue are highly enriched in a stearoyl/arachidonyl (C38:4) diacylgycerol backbone. However, mammalian cells grown in culture typically contain more diverse molecular species of phosphoinositides, characterised by a reduction in arachidonyl content in the sn-2 position. We have analysed the phosphoinositide species in MCF10a cells grown in culture by mass spectrometry. Under either serum or serum starved conditions the most abundant species of PI, PIP, PIP2 and PIP3 had masses which corresponded to C36:2, C38:4, C38:3, C38:2 and C36:1 diacylglycerol backbones and the relative proportions of each molecular species were broadly similar between each phosphoinositide class (approx...
September 2016: Advances in Biological Regulation
Shahram Bahrami, Finn Drabløs
Immediate-early genes (IEGs) can be activated and transcribed within minutes after stimulation, without the need for de novo protein synthesis, and they are stimulated in response to both cell-extrinsic and cell-intrinsic signals. Extracellular signals are transduced from the cell surface, through receptors activating a chain of proteins in the cell, in particular extracellular-signal-regulated kinases (ERKs), mitogen-activated protein kinases (MAPKs) and members of the RhoA-actin pathway. These communicate through a signaling cascade by adding phosphate groups to neighboring proteins, and this will eventually activate and translocate TFs to the nucleus and thereby induce gene expression...
May 13, 2016: Advances in Biological Regulation
Pann-Ghill Suh, Lucio Cocco
No abstract text is available yet for this article.
May 2016: Advances in Biological Regulation
Varnavas D Mouchlis, Edward A Dennis
Studying phospholipases A2 (PLA2s) is a challenging task since they act on membrane-like aggregated substrates and not on monomeric phospholipids. Multidisciplinary approaches that include hydrogen/deuterium exchange mass spectrometry (DXMS) and computational techniques have been employed with great success in order to address important questions about the mode of interactions of PLA2 enzymes with membranes, phospholipid substrates and inhibitors. Understanding the interactions of PLA2s is crucial since these enzymes are the upstream regulators of the eicosanoid pathway liberating free arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA)...
May 2016: Advances in Biological Regulation
Suzanne Scarlata, Osama Garwain, Leo Williams, Imanol Gonzalez Burguera, Barbara Rosati, Shriya Sahu, Yuanjian Guo, Finly Philip, Urszula Golebiewska
Phosphoinositide-specific-phospholipase Cβ (PLCβ) is the main effector of Gαq stimulation which is coupled to receptors that bind acetylcholine, bradykinin, dopamine, angiotensin II as well as other hormones and neurotransmitters. Using a yeast two-hybrid and other approaches, we have recently found that the same region of PLCβ that binds Gαq also interacts with Component 3 Promoter of RNA induced silencing complex (C3PO), which is required for efficient activity of the RNA-induced silencing complex. In purified form, C3PO competes with Gαq for PLCβ binding and at high concentrations can quench PLCβ activation...
May 2016: Advances in Biological Regulation
Tibor Rohacs
Somatosensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are responsible for detecting thermal and tactile stimuli. They are also the primary neurons mediating pain and itch. A large number of cell surface receptors in these neurons couple to phospholipase C (PLC) enzymes leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and the generation of downstream signaling molecules. These neurons also express many different ion channels, several of which are regulated by phosphoinositides...
May 2016: Advances in Biological Regulation
Colin Valet, Sonia Severin, Gaëtan Chicanne, Pierre Alexandre Laurent, Frédérique Gaits-Iacovoni, Marie-Pierre Gratacap, Bernard Payrastre
Blood platelets play a pivotal role in haemostasis and are strongly involved in arterial thrombosis, a leading cause of death worldwide. Besides their critical role in pathophysiology, platelets represent a valuable model to investigate, both in vitro and in vivo, the biological roles of different branches of the phosphoinositide metabolism, which is highly active in platelets. While the phospholipase C (PLC) pathway has a crucial role in platelet activation, it is now well established that at least one class I phosphoinositide 3-kinase (PI3K) is also mandatory for proper platelet functions...
May 2016: Advances in Biological Regulation
Maria-Luisa Giudici, Jonathan H Clarke, Robin F Irvine
The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are an important family of enzymes, whose physiological roles are being teased out by a variety of means. Phosphatidylinositol-5-phosphate 4-kinase γ (PI5P4Kγ) is especially intriguing as its in vitro activity is very low. Here we review what is known about this enzyme and discuss some recent advances towards an understanding of its physiology. Additionally, the effects of the ATP-competitive inhibitor I-OMe Tyrphostin AG-538 on all three mammalian PI5P4Ks was explored, including two PI5P4Kγ mutants with altered ATP- or PI5P-binding sites...
May 2016: Advances in Biological Regulation
Siti Nornadhirah Amdani, Marc Yeste, Celine Jones, Kevin Coward
The development of a mammalian embryo is initiated by a sequence of molecular events collectively referred to as 'oocyte activation' and regulated by the release of intracellular calcium in the ooplasm. Over the last decade, phospholipase C zeta (PLCζ), a sperm protein introduced into the oocyte upon gamete fusion, has gained almost universal acceptance as the protein factor responsible for initiating oocyte activation. A large body of consistent and reproducible evidence, from both biochemical and clinical settings, confers support for the role of PLCζ in this fundamental biological context, which has significant ramifications for the management of human male infertility...
May 2016: Advances in Biological Regulation
Jaewang Ghim, Chaithanya Chelakkot, Yoe-Sik Bae, Pann-Ghill Suh, Sung Ho Ryu
Phospholipase D2 (PLD2) is a lipid-signaling enzyme that produces the signaling molecule phosphatidic acid (PA) by catalyzing the hydrolysis of phosphatidylcholine (PC). The molecular characteristics of PLD2, the mechanisms of regulation of its activity, its functions in the signaling pathway involving PA and binding partners, and its role in cellular physiology have been extensively studied over the past decades. Although several potential roles of PLD2 have been proposed based on the results of molecular and cell-based studies, the pathophysiological functions of PLD2 in vivo have not yet been fully investigated at the organismal level...
May 2016: Advances in Biological Regulation
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