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https://www.readbyqxmd.com/read/27834733/quantitative-proteomics-reveals-fundamental-regulatory-differences-in-oncogenic-hras-and-idh1-driven-astrocytoma
#1
Sophia Doll, Anatoly Urisman, Juan A Oses-Prieto, David Arnott, Alma L Burlingame
Glioblastoma multiformes (GBMs) are high-grade astrocytomas and the most common brain malignancies. Primary GBMs are often associated with disturbed RAS signaling, and expression of oncogenic HRAS results in a malignant phenotype in glioma cell lines. Secondary GBMs arise from lower-grade astrocytomas, have slower progression than primary tumors, and contain IDH1 mutations in over 70% of cases. Despite significant amount of accumulating genomic and transcriptomic data, the fundamental mechanistic differences of gliomagenesis in these two types of high-grade astrocytoma remain poorly understood...
November 10, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27794539/human-r1441c-lrrk2-regulates-the-synaptic-vesicle-proteome-and-phosphoproteome-in-a-drosophila-model-of-parkinson-s-disease
#2
Shariful Islam, Hendrik Nolte, Wright Jacob, Anna B Ziegler, Stefanie Pütz, Yael Grosjean, Karolina Szczepanowska, Aleksandra Trifunovic, Thomas Braun, Hermann Heumann, Rolf Heumann, Bernhard Hovemann, Darren J Moore, Marcus Krüger
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinson's disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model...
October 29, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27782176/functional-kinomics-establishes-a-critical-node-of-volume-sensitive-cation-cl-cotransporter-regulation-in-the-mammalian-brain
#3
Jinwei Zhang, Geng Gao, Gulnaz Begum, Jinhua Wang, Arjun R Khanna, Boris E Shmukler, Gerrit M Daubner, Paola de Los Heros, Paul Davies, Joby Varghese, Mohammad Iqbal H Bhuiyan, Jinjing Duan, Jin Zhang, Daniel Duran, Seth L Alper, Dandan Sun, Stephen J Elledge, Dario R Alessi, Kristopher T Kahle
Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr(991)/Thr(1048) phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD)...
October 26, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27752081/corticotropin-releasing-factor-overexpression-gives-rise-to-sex-differences-in-alzheimer-s-disease-related-signaling
#4
D A Bangasser, H Dong, J Carroll, Z Plona, H Ding, L Rodriguez, C McKennan, J G Csernansky, S H Seeholzer, R J Valentino
Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles...
October 18, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27748686/spinocerebellar-ataxia-type-12-clues-to-pathogenesis
#5
Rachael L Cohen, Russell L Margolis
PURPOSE OF REVIEW: Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disease characterized by tremor, gait abnormalities, and neuropsychiatric syndromes. The location of the causative CAG/CTG expansion mutation in PPP2R2B, a gene encoding regulatory units of the protein phosphatase 2A, may provide unique insights into the pathogenesis of neurodegeneration. RECENT FINDINGS: The first neuropathological examination of a brain from an SCA12 patient revealed both cerebellar and cerebral cortical atrophy, with a noted loss of Purkinje cells and no evidence of polyglutamine aggregates...
December 2016: Current Opinion in Neurology
https://www.readbyqxmd.com/read/27708245/chronic-low-dose-rate-ionising-radiation-affects-the-hippocampal-phosphoproteome-in-the-apoe-alzheimer-s-mouse-model
#6
Stefan J Kempf, Dirk Janik, Zarko Barjaktarovic, Ignacia Braga-Tanaka Iii, Satoshi Tanaka, Frauke Neff, Anna Saran, Martin R Larsen, Soile Tapio
Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates...
September 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27703031/quantitative-phosphoproteomic-analysis-identifies-the-critical-role-of-jnk1-in-neuroinflammation-induced-by-japanese-encephalitis-virus
#7
Jing Ye, Hao Zhang, Wen He, Bibo Zhu, Dengyuan Zhou, Zheng Chen, Usama Ashraf, Yanming Wei, Ziduo Liu, Zhen F Fu, Huanchun Chen, Shengbo Cao
Japanese encephalitis virus (JEV) is the leading cause of epidemic encephalitis worldwide. The pathogenesis of JEV is linked to a robust inflammatory response in the central nervous system (CNS). Glial cells are the resident immune cells in the CNS and represent critical effectors of CNS inflammation. To obtain a global overview of signaling events in glial cells during JEV infection, we conducted phosphoproteomics profiling of a JEV-infected glial cell line. We identified 1816 phosphopeptides, corresponding to 1264 proteins, that exhibited a change in phosphorylation status upon JEV infection...
October 4, 2016: Science Signaling
https://www.readbyqxmd.com/read/27636850/comprehensive-quantitative-profiling-of-tau-and-phosphorylated-tau-peptides-in-cerebrospinal-fluid-by-mass-spectrometry-provides-new-biomarker-candidates
#8
Claire L Russell, Vikram Mitra, Karl Hansson, Kaj Blennow, Johan Gobom, Henrik Zetterberg, Mikko Hiltunen, Malcolm Ward, Ian Pike
Aberrant tau phosphorylation is a hallmark in Alzheimer's disease (AD), believed to promote formation of paired helical filaments, the main constituent of neurofibrillary tangles in the brain. While cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine residue 181 (pThr181) are established core biomarkers for AD, the value of alternative phosphorylation sites, which may have more direct relevance to pathology, for early diagnosis is not yet known, largely due to their low levels in CSF and lack of standardized detection methods...
September 14, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27546785/phosphorylation-signals-in-striatal-medium-spiny-neurons
#9
Taku Nagai, Junichiro Yoshimoto, Takayuki Kannon, Keisuke Kuroda, Kozo Kaibuchi
Dopamine signaling in the brain is a complex phenomenon that strongly contributes to emotional behaviors. Medium spiny neurons (MSNs) play a major role in dopamine signaling through dopamine D1 receptors (D1Rs) or dopamine D2 receptors (D2Rs) in the striatum. cAMP/protein kinase A (PKA) regulates phosphorylation signals downstream of D1Rs, which affects the excitability of MSNs, leading to reward-associated emotional expression and memory formation. A combination of phosphoproteomic approaches and the curated KANPHOS database can be used to elucidate the physiological and pathophysiological functions of dopamine signaling and other monoamines...
October 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27362561/quantitative-phosphoproteomics-reveals-signaling-mechanisms-associated-with-rapid-cold-hardening-in-a-chill-tolerant-fly
#10
Nicholas M Teets, David L Denlinger
Rapid cold hardening (RCH) is a physiological adaptation in which brief chilling (minutes to hours) significantly enhances the cold tolerance of insects. RCH allows insects to cope with sudden cold snaps and diurnal variation in temperature, but the mechanistic basis of this rapid stress response is poorly understood. Here, we used phosphoproteomics to identify phosphorylation-mediated signaling events that are regulated by chilling that induces RCH. Phosphoproteomic changes were measured in both brain and fat bodies, two tissues that are essential for sensing cold and coordinating RCH at the organismal level...
August 5, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27354287/network-modeling-identifies-patient-specific-pathways-in-glioblastoma
#11
Nurcan Tuncbag, Pamela Milani, Jenny L Pokorny, Hannah Johnson, Terence T Sio, Simona Dalin, Dennis O Iyekegbe, Forest M White, Jann N Sarkaria, Ernest Fraenkel
Glioblastoma is the most aggressive type of malignant human brain tumor. Molecular profiling experiments have revealed that these tumors are extremely heterogeneous. This heterogeneity is one of the principal challenges for developing targeted therapies. We hypothesize that despite the diverse molecular profiles, it might still be possible to identify common signaling changes that could be targeted in some or all tumors. Using a network modeling approach, we reconstruct the altered signaling pathways from tumor-specific phosphoproteomic data and known protein-protein interactions...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27196784/quantitative-phosphoproteomics-reveals-wee1-kinase-as-a-therapeutic-target-in-a-model-of-proneural-glioblastoma
#12
Rebecca S Lescarbeau, Liang Lei, Katrina K Bakken, Peter A Sims, Jann N Sarkaria, Peter Canoll, Forest M White
Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors...
June 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27130120/preparation-of-ti-4-immobilized-modified-silica-capillary-trapping-column-for-on-line-selective-enrichment-of-phosphopeptides
#13
Huili Yang, Chunhui Deng, Xiangmin Zhang
In this work, we have developed Ti(4+)-immobilized capillary trapping column (250μm i.d.) for highly specific on-line enrichment of phosphopeptides in the bio-samples. It minimizes the sample loss and improves the effectiveness of phosphopeptide detection that the limit of detection is as low as 1fmol/μL. It is successfully applied to the detection of phosphopeptides from complex biological samples, such as skim milk, human serum and mouse brain. The results indicate that the Ti(4+)-immobilized capillary trapping column is time-effective and has the great potential of application in low-abundance phosphopeptides on-line analysis...
June 1, 2016: Talanta
https://www.readbyqxmd.com/read/27115346/analysis-of-protein-phosphorylation-in-nerve-terminal-reveals-extensive-changes-in-active-zone-proteins-upon-exocytosis
#14
Mahdokht Kohansal-Nodehi, John Je Chua, Henning Urlaub, Reinhard Jahn, Dominika Czernik
Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats...
2016: ELife
https://www.readbyqxmd.com/read/27094720/differential-proteome-and-phosphoproteome-may-impact-cell-signaling-in-the-corpus-callosum-of-schizophrenia-patients
#15
Verônica M Saia-Cereda, Juliana S Cassoli, Andrea Schmitt, Peter Falkai, Daniel Martins-de-Souza
Schizophrenia is a multifactorial disease in both clinical and molecular terms. Thus, depicting the molecular aspects of the disease will contribute to the understanding of its biochemical mechanisms and consequently may lead to the development of new treatment strategies. The protein phosphorylation/dephosphorylation switch acts as the main mechanism for regulating cellular signaling. Moreover, approximately onethird of human proteins are phosphorylable. Thus, identifying proteins differentially phosphorylated in schizophrenia postmortem brains may improve our understanding of the molecular basis of brain function in this disease...
April 16, 2016: Schizophrenia Research
https://www.readbyqxmd.com/read/27074656/brief-isoflurane-anesthesia-produces-prominent-phosphoproteomic-changes-in-the-adult-mouse-hippocampus
#16
Samuel Kohtala, Wiebke Theilmann, Tomi Suomi, Henna-Kaisa Wigren, Tarja Porkka-Heiskanen, Laura L Elo, Anne Rokka, Tomi Rantamäki
Anesthetics are widely used in medical practice and experimental research, yet the neurobiological basis governing their effects remains obscure. We have here used quantitative phosphoproteomics to investigate the protein phosphorylation changes produced by a 30 min isoflurane anesthesia in the adult mouse hippocampus. Altogether 318 phosphorylation alterations in total of 237 proteins between sham and isoflurane anesthesia were identified. Many of the hit proteins represent primary pharmacological targets of anesthetics...
June 15, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27070703/single-cell-phosphoproteomics-resolves-adaptive-signaling-dynamics-and-informs-targeted-combination-therapy-in-glioblastoma
#17
Wei Wei, Young Shik Shin, Min Xue, Tomoo Matsutani, Kenta Masui, Huijun Yang, Shiro Ikegami, Yuchao Gu, Ken Herrmann, Dazy Johnson, Xiangming Ding, Kiwook Hwang, Jungwoo Kim, Jian Zhou, Yapeng Su, Xinmin Li, Bruno Bonetti, Rajesh Chopra, C David James, Webster K Cavenee, Timothy F Cloughesy, Paul S Mischel, James R Heath, Beatrice Gini
Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest...
April 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27067626/unbiased-identification-of-substrates-of-protein-tyrosine-phosphatase-ptp-3-in-c-elegans
#18
Christopher J Mitchell, Min-Sik Kim, Jun Zhong, Raja Sekhar Nirujogi, Anjun K Bose, Akhilesh Pandey
The leukocyte antigen related (LAR) family of receptor-like protein tyrosine phosphatases has three members in humans - PTPRF, PTPRD and PTPRS - that have been implicated in diverse processes including embryonic development, inhibition of cell growth and axonal guidance. Mutations in the LAR family are associated with developmental defects such as cleft palate as well as various cancers including breast, neck, lung, colon and brain. Although this family of tyrosine phosphatases is important for many developmental processes, little is known of their substrates...
June 2016: Molecular Oncology
https://www.readbyqxmd.com/read/27030266/roles-of-us8a-and-its-phosphorylation-mediated-by-us3-in-herpes-simplex-virus-1-pathogenesis
#19
Akihisa Kato, Tomoko Ando, Shinya Oda, Mizuki Watanabe, Naoto Koyanagi, Jun Arii, Yasushi Kawaguchi
UNLABELLED: The herpes simplex virus 1 (HSV-1) Us8A gene overlaps the gene that encodes glycoprotein E (gE). Previous studies have investigated the roles of Us8A in HSV-1 infection using null mutations in Us8A and gE; therefore, the role of Us8A remains to be elucidated. In this study, we investigated the function of Us8A and its phosphorylation at serine 61 (Ser-61), which we recently identified as a phosphorylation site by mass spectrometry-based phosphoproteomic analysis of HSV-1-infected cells, in HSV-1 pathogenesis...
June 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27009214/quantitative-phosphoproteomics-reveals-wee1-kinase-as-a-therapeutic-target-in-a-model-of-proneural-glioblastoma
#20
Rebecca S Lescarbeau, Liang Lei, Katrina K Bakken, Peter A Sims, Jann N Sarkaria, Peter Canoll, Forest M White
Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors...
March 23, 2016: Molecular Cancer Therapeutics
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