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Jikui Guan, Susanne Fransson, Joachim Tetteh T Siaw, Diana Treis, Jimmy Van den Eynden, Damini Chand, Ganesh Umapathy, Petter Svenberg, Kristina Ruuth, Sandra Wessman, Alia Shamikh, Hans Jacobsson, Lena Gordon, Jakob Stenman, Erik Larsson, Par-Johan Svensson, Magnus Hansson, Tommy Martinsson, Per Kogner, Ruth H Palmer, Bengt Hallberg
Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options...
June 15, 2018: Cold Spring Harbor Molecular Case Studies
Kimberly K Fong, Alex Zelter, Beth Graczyk, Jill M Hoyt, Michael Riffle, Richard Johnson, Michael J MacCoss, Trisha N Davis
Phosphorylation regulates yeast spindle pole body (SPB) duplication and separation and likely regulates microtubule nucleation. We report a phosphoproteomic analysis using tandem mass spectrometry of enriched Saccharomyces cerevisiae SPBs for two cell cycle arrests, G1/S and the mitotic checkpoint, expanding on previously reported phosphoproteomic data sets. We present a novel phosphoproteomic state of SPBs arrested in G1/S by a cdc4-1 temperature sensitive mutation, with particular focus on phosphorylation events on the γ-tubulin small complex (γ-TuSC)...
June 14, 2018: Biology Open
Ashutosh Rai, B D Radotra, K K Mukherjee, S K Gupta, Pinaki Dutta
Here we describe data of a comprehensive phosphoproteomic evaluation of 20 non-functioning pituitary adenomas (NFPAs). Peptides from 20 tumor samples were enriched with TiO2 beads and fractioned using bRPLC and subjected to high throughput LC-MS/MS-Orbitrap Fusion™ Tribrid™ Mass Spectrometer for analysis. Upto 5 precursor ions were selected for MS/MS analysis. Data was analyzed using MASCOT and SEQUEST. Bioinformatics tools Phosphosite Plus, Gene Ontology, DAVID, and KEGG were used to determine the biological significance of identified phosphoproteins...
June 2018: Data in Brief
Zhiqiang Wang, Jing Ma, Chika Miyoshi, Yuxin Li, Makito Sato, Yukino Ogawa, Tingting Lou, Chengyuan Ma, Xue Gao, Chiyu Lee, Tomoyuki Fujiyama, Xiaojie Yang, Shuang Zhou, Noriko Hotta-Hirashima, Daniela Klewe-Nebenius, Aya Ikkyu, Miyo Kakizaki, Satomi Kanno, Liqin Cao, Satoru Takahashi, Junmin Peng, Yonghao Yu, Hiromasa Funato, Masashi Yanagisawa, Qinghua Liu
Sleep and wake have global effects on brain physiology, from molecular changes1-4 and neuronal activities to synaptic plasticity3-7 . Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep8-11 . Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep...
June 13, 2018: Nature
Michael Charles Lanz, Susannah Oberly, Ethan James Sanford, Sushma Sharma, Andrei Chabes, Marcus Bustamante Smolka
The Mec1/ATR kinase coordinates multiple cellular responses to replication stress. In addition to its canonical role in activating the checkpoint kinase Rad53, Mec1 also plays checkpoint-independent roles in genome maintenance that are not well understood. Here we used a combined genetic-phosphoproteomic approach to manipulate Mec1 activation and globally monitor Mec1 signaling, allowing us to delineate distinct checkpoint-independent modes of Mec1 action. Using cells in which endogenous Mec1 activators were genetically ablated, we found that expression of "free" Mec1 activation domains (MADs) can robustly activate Mec1 and rescue the severe DNA replication and growth defects of these cells back to wild-type levels...
June 13, 2018: Genes & Development
Naoto Koyanagi, Akihisa Kato, Kosuke Takeshima, Yuhei Maruzuru, Hiroko Kozuka-Hata, Masaaki Oyama, Jun Arii, Yasushi Kawaguchi
UL13 proteins are serine/threonine protein kinases encoded by herpes simplex virus HSV-1 and HSV-2. Although the downstream effects of the HSV protein kinases, mostly those of HSV-1 UL13, have been reported, there is a lack of information on how these viral protein kinases are regulated in HSV-infected cells. In this study, we used a large-scale phosphoproteomic analysis of HSV-2-infected cells to identify a physiological phosphorylation site in HSV-2 UL13 (i.e., Ser-18), and investigated the significance of phosphorylation of this site in HSV-2-infected cell cultures and mice...
June 13, 2018: Journal of Virology
Swati Dey, Deeptankar DeMazumder, Agnieszka Sidor, D B Foster, Brian O'Rourke
<u>Rationale:</u> Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored...
June 13, 2018: Circulation Research
Isabelle Re Nett, Carla Mulas, Laurent Gatto, Kathryn S Lilley, Austin Smith
Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling is implicated in initiation of embryonic stem (ES) cell differentiation. The pathway is subject to complex feedback regulation. Here, we examined the ERK-responsive phosphoproteome in ES cells and identified the negative regulator RSK1 as a prominent target. We used CRISPR/Cas9 to create combinatorial mutations in RSK family genes. Genotypes that included homozygous null mutations in Rps6ka1, encoding RSK1, resulted in elevated ERK phosphorylation...
June 12, 2018: EMBO Reports
Stephanie Post, Galina Karashchuk, John D Wade, Waseem Sajid, Pierre De Meyts, Marc Tatar
Insulin and IGF signaling (IIS) is a complex system that controls diverse processes including growth, development, metabolism, stress responses, and aging. Drosophila melanogaster IIS is propagated by eight Drosophila insulin-like peptides (DILPs), homologs of both mammalian insulin and IGFs, with various spatiotemporal expression patterns and functions. DILPs 1-7 are thought to act through a single Drosophila insulin/IGF receptor, InR, but it is unclear how the DILPs thereby mediate a range of physiological phenotypes...
2018: Frontiers in Endocrinology
Ina Nepstad, Kimberley J Hatfield, Elise Aasebø, Maria Hernandez-Valladares, Annette K Brenner, Sushma Bartaula-Brevik, Frode Berven, Frode Selheim, Jørn Skavland, Bjørn Tore Gjertsen, Håkon Reikvam, Øystein Bruserud
OBJECTIVES: Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. The aim of the study was to compare constitutive PI3K-Akt-mTOR activation of primary AML cells for a large group of unselected patients. METHODS: We investigated expression and phosphorylation of 18 mediators in the PI3K-Akt-mTOR main track by flow cytometry for AML cells derived from 77 patients, and compared this with global gene expression profiles, proteomic and transcriptomic profiles, and susceptibility to antileukemic agents...
June 11, 2018: Expert Opinion on Therapeutic Targets
Karl W Barber, Paul Muir, Richard V Szeligowski, Svetlana Rogulina, Mark Gerstein, Jeffrey R Sampson, Farren J Isaacs, Jesse Rinehart
Post-translational phosphorylation is essential to human cellular processes, but the transient, heterogeneous nature of this modification complicates its study in native systems. We developed an approach to interrogate phosphorylation and its role in protein-protein interactions on a proteome-wide scale. We genetically encoded phosphoserine in recoded E. coli and generated a peptide-based heterologous representation of the human serine phosphoproteome. We designed a single-plasmid library encoding >100,000 human phosphopeptides and confirmed the site-specific incorporation of phosphoserine in >36,000 of these peptides...
June 11, 2018: Nature Biotechnology
Christoph N Schlaffner, Georg J Pirklbauer, Andreas Bender, Judith A J Steen, Jyoti S Choudhary
Cross-talk between genes, transcripts, and proteins is the key to cellular responses; hence, analysis of molecular levels as distinct entities is slowly being extended to integrative studies to enhance the understanding of molecular dynamics within cells. Current tools for the visualization and integration of proteomics with other omics datasets are inadequate for large-scale studies. Furthermore, they only capture basic sequence identify, discarding post-translational modifications and quantitation. To address these issues, we developed PoGo to map peptides with associated post-translational modifications and quantification to reference genome annotation...
May 22, 2018: Journal of Visualized Experiments: JoVE
Eve-Ellen Govek, Zhuhao Wu, Devrim Acehan, Henrik Molina, Keith Rivera, Xiaodong Zhu, Yin Fang, Marc Tessier-Lavigne, Mary Elizabeth Hatten
CNS cortical histogenesis depends on polarity signaling pathways that regulate cell adhesion and motility. Here we report that conditional deletion of the Rho GTPase Cdc42 in cerebellar granule cell precursors (GCPs) results in abnormalities in cerebellar foliation revealed by iDISCO clearing methodology, a loss of columnar organization of proliferating GCPs in the external germinal layer (EGL), disordered parallel fiber organization in the molecular layer (ML), and a failure to extend a leading process and form a neuron-glial junction during migration along Bergmann glia (BG)...
March 23, 2018: iScience
Peter Hofsteen, Aaron Mark Robitaille, Nicholas Strash, Nathan Palpant, Randall T Moon, Lil Pabon, Charles E Murry
Cardiac development requires coordinated biphasic regulation of the WNT/β-catenin signaling pathway. By intersecting gene expression and loss-of-function siRNA screens we identified Alpha Protein Kinase 2 (ALPK2) as a candidate negative regulator of WNT/β-catenin signaling in cardiogenesis. In differentiating human embryonic stem cells (hESCs), ALPK2 is highly induced as hESCs transition from mesoderm to cardiac progenitors. Using antisense knockdown and CRISPR/Cas9 mutagenesis in hESCs and zebrafish, we demonstrate that ALPK2 promotes cardiac function and cardiomyocyte differentiation...
April 27, 2018: iScience
Xu Ye, Ting Pan, Dang Wang, Liurong Fang, Jun Ma, Xinyu Zhu, Yanling Shi, Keshan Zhang, Haixue Zheng, Huanchun Chen, Kui Li, Shaobo Xiao
Foot-and-mouth disease (FMD) is a highly contagious, severe viral illness notifiable to the World Organization for Animal Health. The causative agent, FMD virus (FMDV), replicates rapidly and efficiently inhibits host translation and the innate immune response for it has developed multiple tactics to evade host defenses and takes over gene expression machinery in the host cell. Here, we report a systemic analysis of the proteome and phosphoproteome of FMDV-infected cells. Bioinformatics analysis suggested that FMDV infection shuts off host cap-dependent translation, but leaves intact internal ribosome entry site (IRES)-mediated translation for viral proteins...
2018: Frontiers in Immunology
Valentina Siino, Antonella Amato, Francesca Di Salvo, Gaetano Felice Caldara, Marcello Filogamo, Peter James, Sonya Vasto
Obesity is closely associated to several diseases such as type 2 diabetes, cardiovascular disease, hepatic steatosis, airway disease, neurodegeneration, biliary diseases and certain cancers. It is, therefore, of importance to assess the role of nutrition in disease prevention as well as its effect in the course of such pathologies. In the present study, we addressed the impact of the exposure to different obesogenic diets in the mice brains phosphoproteome. To analyze if the obesity could be able to modify the protein pattern expression of brain neurons, obesity was induced in two different groups of mice...
May 1, 2018: Journal of Nutritional Biochemistry
Kou Motani, Hidetaka Kosako
Protein phosphorylation is one of the most common post-translational modifications in eukaryotes and can regulate diverse properties of proteins. Protein kinases are encoded by more than 500 genes in higher eukaryotes and play central roles in various cellular signaling pathways. Consequently, genetic abnormalities of protein kinases have been implicated in many diseases. To fully understand the complex phosphorylation-mediated signaling networks, it is important to globally identify and functionally characterize in vivo substrates of individual protein kinases...
June 5, 2018: Biochimica et Biophysica Acta
Zekun Liu, Qing-Bin Zhang, Chen Bu, Dawei Wang, Kai Yu, Zhixue Gan, Jianfeng Chang, Zhongyi Cheng, Zexian Liu
Stem cell differentiation is a complex biological process controlled by a series of functional protein clusters and signaling transductions especially metabolism related pathways. Although previous studies have quantified the proteome and phosphoproteome for stem cell differentiation, the investigation of acylation-mediated regulation is still absent. In this study, we quantitatively profiled the proteome, acetylome and succinylome in pluripotent human embryonic stem cells (hESCs) and differentiated hepatocyte-like cells (HLCs)...
June 8, 2018: Journal of Proteome Research
Siyuan Tan, Jundong Wang, Qiang Han, Qionglin Liang, Mingyu Ding
A novel polydopamine coated three-dimensional porous graphene aerogel sorbent carrying immobilized titanium(IV) ions (denoted as Ti4+ @PDA@GA) was fabricated without using an organic solvent. The material is shown to be a viable carbon foam type of monolithic sorbent for selective lab-in-syringe enrichment of phosphoproteins and phosphopeptides. The phosphoproteins can be separated from a sample by aspiration and then bind to the sorbent. The analytes then can be dispensed within 5 min. The weight percent of titanium in the monolith typically is 14%, and the absorption capacities for the model proteins β-casein and κ-casein are 1300 and 1345 mg g-1 , respectively...
June 6, 2018: Mikrochimica Acta
Sébastien De Landtsheer, Philippe Lucarelli, Thomas Sauter
Understanding the functional properties of cells of different origins is a long-standing challenge of personalized medicine. Especially in cancer, the high heterogeneity observed in patients slows down the development of effective cures. The molecular differences between cell types or between healthy and diseased cellular states are usually determined by the wiring of regulatory networks. Understanding these molecular and cellular differences at the systems level would improve patient stratification and facilitate the design of rational intervention strategies...
2018: Frontiers in Physiology
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