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https://www.readbyqxmd.com/read/29314504/serine-threonine-kinase-ppka-coordinates-the-interplay-between-t6ss2-activation-and-quorum-sensing-in-the-marine-pathogen-vibrio-alginolyticus
#1
Zhen Yang, Xiaohui Zhou, Yue Ma, Mian Zhou, Matthew K Waldor, Yuanxing Zhang, Qiyao Wang
Type VI secretion systems (T6SS) are multiprotein secretion machines that can mediate killing of bacterial cells and thereby modify the composition of bacterial communities. The mechanisms that control the production of and secretion of these killing machines are incompletely understood, although quorum sensing (QS) and the PpkA kinase modulate T6SS activity in some organisms. Here we investigated control the T6S in the marine organism Vibrio alginolyticus EPGS, which encodes two T6SS systems (T6SS1 and T6SS2)...
January 4, 2018: Environmental Microbiology
https://www.readbyqxmd.com/read/29298809/sucrose-non-fermenting-related-kinase-regulates-both-adipose-inflammation-and-energy-homeostasis-in-mice-and-humans
#2
Jie Li, Bin Feng, Yaohui Nie, Ping Jiao, Xiaochen Lin, Mengna Huang, Ran An, Qin He, Huilin Emily Zhou, Arthur Salomon, Kirsten S Sigrist, Zhidan Wu, Simin Liu, Haiyan Xu
Sucrose non-fermenting related kinase (SNRK) is a member of AMPK-related kinase family and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white (WAT) and brown adipose tissue (BAT) but adipose SNRK expression level diminishes in obesity. In the current study, we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival since SNRK global deficient pups die within 24 hours after birth...
January 3, 2018: Diabetes
https://www.readbyqxmd.com/read/29280302/combining-phosphoproteomics-datasets-and-literature-information-to-reveal-the-functional-connections-in-a-cell-phosphorylation-network
#3
REVIEW
Francesca Sacco, Livia Perfetto, Gianni Cesareni
Protein phosphorylation modulates many biological processes. However, the characterization of the complex regulatory circuits underlying cell response to external and internal stimuli is still limited by our inability to describe the phosphorylation network on a global scale. Modern mass spectrometry-based phosphoproteomics allows monitoring tens of thousands of phosphorylation sites in multiple conditions, making the approach ideal to explore signaling pathways mediated by phosphorylation. Here we review recent advances in phosphoproteomics and discuss some of the computational approaches developed to facilitate extraction of signaling information from these datasets...
December 26, 2017: Proteomics
https://www.readbyqxmd.com/read/29279356/adaptive-and-reversible-resistance-to-kras-inhibition-in-pancreatic-cancer-cells
#4
Pan-Yu Chen, Mandar D Muzumdar, Kimberly Judith Dorans, Rebecca A Robbins, Arjun Bhutkar, Amanda M Del Rosario, Philipp Mertins, Jana Qiao, Claudia Schäfer, Frank B Gertler, Steven A Carr, Tyler Jacks
Activating mutations in KRAS are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and the key drivers of its initiation and progression. Longstanding efforts to develop novel KRAS inhibitors have been based on the assumption that PDAC cells are addicted to activated KRAS, but this assumption remains controversial. In this study, we analyzed the requirement of endogenous Kras to maintain survival of murine PDAC cells, using an inducible shRNA-based system that enables temporal control of Kras expression...
December 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/29276520/combined-15n-labeling-and-tandemmoac-quantifies-phosphorylation-of-map-kinase-substrates-downstream-of-mkk7-in-arabidopsis
#5
Nicola V Huck, Franz Leissing, Petra Majovsky, Matthias Buntru, Christina Aretz, Mirkko Flecken, Jörg P J Müller, Simon Vogel, Stefan Schillberg, Wolfgang Hoehenwarter, Uwe Conrath, Gerold J M Beckers
Reversible protein phosphorylation is a widespread posttranslational modification that plays a key role in eukaryotic signal transduction. Due to the dynamics of protein abundance, low stoichiometry and transient nature of protein phosphorylation, the detection and accurate quantification of substrate phosphorylation by protein kinases remains a challenge in phosphoproteome research. Here, we combine tandem metal-oxide affinity chromatography (tandemMOAC) with stable isotope 15N metabolic labeling for the measurement and accurate quantification of low abundant, transiently phosphorylated peptides by mass spectrometry...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29262332/dynamic-metabolomics-reveals-that-insulin-primes-the-adipocyte-for-glucose-metabolism
#6
James R Krycer, Katsuyuki Yugi, Akiyoshi Hirayama, Daniel J Fazakerley, Lake-Ee Quek, Richard Scalzo, Satoshi Ohno, Mark P Hodson, Satsuki Ikeda, Futaba Shoji, Kumi Suzuki, Westa Domanova, Benjamin L Parker, Marin E Nelson, Sean J Humphrey, Nigel Turner, Kyle L Hoehn, Gregory J Cooney, Tomoyoshi Soga, Shinya Kuroda, David E James
Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29249658/mechanisms-connecting-the-conserved-protein-kinases-ssp1-kin1-and-pom1-in-fission-yeast-cell-polarity-and-division
#7
Mid Eum Lee, Scott F Rusin, Nicole Jenkins, Arminja N Kettenbach, James B Moseley
Connections between the protein kinases that function within complex cell polarity networks are poorly understood. Rod-shaped fission yeast cells grow in a highly polarized manner, and genetic screens have identified many protein kinases, including the CaMKK-like Ssp1 and the MARK/PAR-1 family kinase Kin1, that are required for polarized growth and cell shape, but their functional mechanisms and connections have been unknown [1-5]. We found that Ssp1 promotes cell polarity by phosphorylating the activation loop of Kin1...
December 7, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29234155/analysis-of-neuronal-phosphoproteome-reveals-pink1-regulation-of-bad-function-and-cell-death
#8
Huida Wan, Bin Tang, Xun Liao, Qiufang Zeng, Zhuohua Zhang, Lujian Liao
PINK1 mutations that disrupt its kinase activity cause autosomal recessive early onset Parkinson's disease (PD). Although research in recent years has elucidated a PINK1-Parkin pathway of mitophagy activation that requires PINK1 kinase activity, mitophagy-independent functions of PINK1 and their possible roles in PD pathogenesis have been proposed. Using an unbiased quantitative mass spectrometry approach to analyze the phosphoproteome in primary neurons from wild type and Pink1 knockout mice after mitochondrial depolarization, we uncovered PINK1-regulated phosphorylation sites, which involve coordinated activation of multiple signaling pathways that control cellular response to stress...
December 12, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29233185/phosphoproteomics-reveals-network-rewiring-to-a-pro-adhesion-state-in-annexin-1-deficient-mammary-epithelial-cells
#9
Asfa Alli-Shaik, Sheena Wee, Lina H K Lim, Jayantha Gunaratne
BACKGROUND: Annexin-1 (ANXA1) plays pivotal roles in regulating various physiological processes including inflammation, proliferation and apoptosis, and deregulation of ANXA1 functions has been associated with tumorigenesis and metastasis events in several types of cancer. Though ANXA1 levels correlate with breast cancer disease status and outcome, its distinct functional involvement in breast cancer initiation and progression remains unclear. We hypothesized that ANXA1-responsive kinase signaling alteration and associated phosphorylation signaling underlie early events in breast cancer initiation events and hence profiled ANXA1-dependent phosphorylation changes in mammary gland epithelial cells...
December 12, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29229832/fkbp12-contributes-to-%C3%AE-synuclein-toxicity-by-regulating-the-calcineurin-dependent-phosphoproteome
#10
Gabriela Caraveo, Martin Soste, Valentina Cappelleti, Saranna Fanning, Damian B van Rossum, Luke Whitesell, Yanmei Huang, Chee Yeun Chung, Valeriya Baru, Sofia Zaichick, Paola Picotti, Susan Lindquist
Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with α-synuclein (α-syn) toxicity, a protein implicated in Parkinson's Disease (PD) and other neurodegenerative diseases. Calcineurin can be inhibited with Tacrolimus through the recruitment and inhibition of the 12-kDa cis-trans proline isomerase FK506-binding protein (FKBP12). Whether calcineurin/FKBP12 represents a native physiologically relevant assembly that occurs in the absence of pharmacological perturbation has remained elusive...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29221171/proteogenomic-analysis-prioritises-functional-single-nucleotide-variants-in-cancer-samples
#11
Shiyong Ma, Ranjeeta Menon, Rebecca C Poulos, Jason W H Wong
Massively parallel DNA sequencing enables the detection of thousands of germline and somatic single nucleotide variants (SNVs) in cancer samples. The functional analysis of these mutations is often carried out through in silico predictions, with further downstream experimental validation rarely performed. Here, we examine the potential of using mass spectrometry-based proteomics data to further annotate the function of SNVs in cancer samples. RNA-seq and whole genome sequencing (WGS) data from Jurkat cells were used to construct a custom database of single amino acid variant (SAAV) containing peptides and identified over 1,000 such peptides in two Jurkat proteomics datasets...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29214152/identification-of-candidate-casein-kinase-2-substrates-in-mitosis-by-quantitative-phosphoproteomics
#12
Scott F Rusin, Mark E Adamo, Arminja N Kettenbach
Protein phosphorylation is a crucial regulatory mechanism that controls many aspects of cellular signaling. Casein kinase 2 (CK2), a constitutively expressed and active kinase, plays key roles in an array of cellular events including transcription and translation, ribosome biogenesis, cell cycle progression, and apoptosis. CK2 is implicated in cancerous transformation and is a therapeutic target in anti-cancer therapy. The specific and selective CK2 ATP competitive inhibitor, CX-4945 (silmitaseratib), is currently in phase 2 clinical trials...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29211935/a-simple-twist-of-phosphate-immunological-synapse-formation-and-t-cell-receptor-signaling-outcome-in-regulatory-t-cells
#13
Talal A Chatila, Raffaele De Palma
Signaling through the T cell receptor (TCR) regulates T cell homeostasis and effector functions. However, a full accounting of the TCR-coupled signaling networks and how their interplay determines specific functional outcomes remains elusive. Of particular interest are efforts over the last years to elucidate distinctive features of TCR signaling in regulatory T cells (Treg) that may account for some of their unique functional attributes as compared to conventional T (Tconv) cells. In this issue of the European Journal of Immunology, van Ham et al...
December 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29209414/quantitative-in-vivo-phosphoproteomics-reveals-reversible-signaling-processes-during-nitrogen-starvation-and-recovery-in-the-biofuel-model-organism-chlamydomonas-reinhardtii
#14
Valentin Roustan, Shiva Bakhtiari, Pierre-Jean Roustan, Wolfram Weckwerth
Background: Nitrogen deprivation and replenishment induces massive changes at the physiological and molecular level in the green alga Chlamydomonas reinhardtii, including reversible starch and lipid accumulation. Stress signal perception and acclimation involves transient protein phosphorylation. This study aims to provide the first experimental phosphoprotein dataset for the adaptation of C. reinhardtii during nitrogen depletion and recovery growth phases and its impact on lipid accumulation...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/29209046/cdc7-dbf4-mediated-phosphorylation-of-hsp90-s164-stabilizes-hsp90-hclk2-mrn-complex-to-enhance-atr-atm-signaling-that-overcomes-replication-stress-in-cancer
#15
An Ning Cheng, Chi-Chen Fan, Yu-Kang Lo, Cheng-Liang Kuo, Hui-Chun Wang, I-Hsin Lien, Shu-Yu Lin, Chung-Hsing Chen, Shih Sheng Jiang, I-Shou Chang, Hsueh-Fen Juan, Ping-Chiang Lyu, Alan Yueh-Luen Lee
Cdc7-Dbf4 kinase plays a key role in the initiation of DNA replication and contributes to the replication stress in cancer. The activity of human Cdc7-Dbf4 kinase remains active and acts as an effector of checkpoint under replication stress. However, the downstream targets of Cdc7-Dbf4 contributed to checkpoint regulation and replication stress-support function in cancer are not fully identified. In this work, we showed that aberrant Cdc7-Dbf4 induces DNA lesions that activate ATM/ATR-mediated checkpoint and homologous recombination (HR) DNA repair...
December 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29199152/low-level-hg2-exposure-modulates-the-b-cell-cytoskeletal-phosphoproteome
#16
Nicholas J Carruthers, Allen J Rosenspire, Joseph A Caruso, Paul M Stemmer
Exposure of Wehi-231 B-cells to Hg2+ for 5min resulted in concentration dependent changes in protein phosphorylations. Phosphorylation was quantified using mass spectrometry to analyze TiO2 and anti-pTyr antibody selected phosphopeptides from Wehi-231 digests. The most frequent and largest amplitude responses to Hg2+ exposure were increased phosphorylation although a decrease was observed for 1% of phosphoproteins detected in the untreated cells. A subset of proteins responded with an increase in phosphorylation to Hg2+ exposure at low micromolar concentrations...
November 30, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/29197866/proteomic-analysis-reveals-a-new-benefit-of-periodic-mechanical-stress-on-chondrocytes
#17
Zeng Li, Zhen Wang, Shun Xu, Wenwei Liang, Weimin Fan
BACKGROUND/AIMS: In recent years, a variety of studies have been performed to investigate the cellular responses of periodic mechanical stress. In our previous studies, we found that periodic mechanical stress can promote proliferation and matrix synthesis through the integrin beta 1-mediated ERK1/2 pathway, and we used proteomic analysis to detect quantitative changes in chondrocytes under periodic mechanical stress. Despite these results, the effects and mechanisms of periodic mechanical stress are still not fully understood, so in this study we extended our study using phosphoproteomic techniques...
December 4, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29196456/deep-coverage-tissue-and-cellular-proteomics-revealed-il-1%C3%AE-can-independently-induce-the-secretion-of-tnf-associated-proteins-from-human-synoviocytes
#18
Shengquan Tang, Suyuan Deng, Jiahui Guo, Xing Chen, Wanling Zhang, Yizhi Cui, Yanzhang Luo, Ziqi Yan, Qing-Yu He, Shan Shen, Tong Wang
Synovitis is a key contributor to the inflammatory environment in osteoarthritis (OA) joints. Currently, the biological therapy of OA is not satisfactory in multiple single-target trials on anti-TNF agents, or IL-1 antagonists. Systems biological understanding of the phosphorylation state in OA synovium is warranted to direct further therapeutic strategies. Therefore, in this study, we compared the human synovial phosphoproteome of the OA with the acute joint fracture subjects. We found that OA synovium had significantly more phosphoproteins, and 82 phosphoproteins could only be specifically found in all the OA samples...
December 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29196224/phosphorylation-of-mig6-negatively-regulates-the-ubiquitination-and-degradation-of-egfr-mutants-in-lung-adenocarcinoma-cell-lines
#19
Gandhi T K Boopathy, Julia Lim Sze Lynn, Sheena Wee, Jayantha Gunaratne, Wanjin Hong
Activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) leads to constitutively active kinase, improves the EGFR stability and promotes malignant transformation in lung adenocarcinoma. Despite the clinical significance, the mechanism by which the increased kinase activity stabilizes the receptor is not completely understood. Using SILAC phosphoproteomic approach, we identify that Mig6 is highly phosphorylated at S256 in EGFR mutants (19del and L858R). Loss of Mig6 contributes to efficient degradation of EGFR wildtype and mutants in lung cancer cells...
November 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29191878/the-target-landscape-of-clinical-kinase-drugs
#20
Susan Klaeger, Stephanie Heinzlmeir, Mathias Wilhelm, Harald Polzer, Binje Vick, Paul-Albert Koenig, Maria Reinecke, Benjamin Ruprecht, Svenja Petzoldt, Chen Meng, Jana Zecha, Katrin Reiter, Huichao Qiao, Dominic Helm, Heiner Koch, Melanie Schoof, Giulia Canevari, Elena Casale, Stefania Re Depaolini, Annette Feuchtinger, Zhixiang Wu, Tobias Schmidt, Lars Rueckert, Wilhelm Becker, Jan Huenges, Anne-Kathrin Garz, Bjoern-Oliver Gohlke, Daniel Paul Zolg, Gian Kayser, Tonu Vooder, Robert Preissner, Hannes Hahne, Neeme Tõnisson, Karl Kramer, Katharina Götze, Florian Bassermann, Judith Schlegl, Hans-Christian Ehrlich, Stephan Aiche, Axel Walch, Philipp A Greif, Sabine Schneider, Eduard Rudolf Felder, Juergen Ruland, Guillaume Médard, Irmela Jeremias, Karsten Spiekermann, Bernhard Kuster
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments...
December 1, 2017: Science
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