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https://www.readbyqxmd.com/read/28176147/antagonism-of-dopamine-d2-receptors-alters-phosphorylation-of-fyn-in-the-rat-medial-prefrontal-cortex
#1
Li-Min Mao, John Q Wang
Several Src family kinase (SFK) members are expressed in the mammalian brain and serve as key kinases in the regulation of a variety of cellular and synaptic events. These SFKs may be subject to the modulation by dopamine, although this topic has been investigated incompletely. In this study, we explored whether dopamine D2 receptors (D2Rs) regulate SFKs in adult rat brains in vivo. We investigated the role of D2Rs in two forebrain areas, the medial prefrontal cortex (mPFC) and hippocampus, since dopamine plays a pivotal role in regulating activity of mPFC and hippocampal neurons and D2Rs are expressed in these regions...
February 7, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28156097/confinement-and-stabilization-of-fyn-sh3-folding-intermediate-mimetics-within-the-cavity-of-the-chaperonin-groel-demonstrated-by-relaxation-based-nmr
#2
David S Libich, Vitali Tugarinov, Rodolfo Ghirlando, G Marius Clore
The interaction of two folding intermediate mimetics of the model protein substrate Fyn SH3 with the chaperonin GroEL, a supramolecular foldase/unfoldase machine, has been investigated by (15)N relaxation-based nuclear magnetic resonance spectroscopy (lifetime line broadening, dark state exchange saturation transfer, and relaxation dispersion). The two mimetics comprise C-terminal truncations of wild-type and triple-mutant (A39V/N53P/V55L) Fyn SH3 in which the C-terminal strand of the SH3 domain is unfolded, while preserving the remaining domain structure...
February 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/28137917/elevating-cxcr7-improves-angiogenic-function-of-epcs-via-akt-gsk-3%C3%AE-fyn-mediated-nrf2-activation-in-diabetic-limb-ischemia
#3
Xiaozhen Dai, Xiaoqing Yan, Jun Zeng, Jing Chen, Yuehui Wang, Jun Chen, Yan Li, Michelle T Barati, Kupper A Wintergerst, Kejian Pan, Matthew A Nystoriak, Daniel J Conklin, Gregg Rokosh, Paul N Epstein, Xiaokun Li, Yi Tan
RATIONALE: Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. OBJECTIVE: To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. METHODS AND RESULTS: CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice...
January 30, 2017: Circulation Research
https://www.readbyqxmd.com/read/28125091/microrna-466-inhibits-tumor-growth-and-bone-metastasis-in-prostate-cancer-by-direct-regulation-of-osteogenic-transcription-factor-runx2
#4
Melissa Colden, Altaf A Dar, Sharanjot Saini, Priya V Dahiya, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Gary Stein, Rajvir Dahiya, Shahana Majid
MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues...
January 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28112226/click-chemistry-based-high-throughput-screening-platform-for-modulators-of-ras-palmitoylation
#5
Lakshmi Ganesan, Peyton Shieh, Carolyn R Bertozzi, Ilya Levental
Palmitoylation is a widespread, reversible lipid modification that has been implicated in regulating a variety of cellular processes. Approximately one thousand proteins are annotated as being palmitoylated, and for some of these, including several oncogenes of the Ras and Src families, palmitoylation is indispensable for protein function. Despite this wealth of disease-relevant targets, there are currently few effective pharmacological tools to interfere with protein palmitoylation. One reason for this lack of development is the dearth of assays to efficiently screen for small molecular inhibitors of palmitoylation...
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096359/%C3%AE-synuclein-binds-and-sequesters-pike-l-into-lewy-bodies-triggering-dopaminergic-cell-death-via-ampk-hyperactivation
#6
Seong Su Kang, Zhentao Zhang, Xia Liu, Fredric P Manfredsson, Li He, P Michael Iuvone, Xuebing Cao, Yi E Sun, Lingjing Jin, Keqiang Ye
The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylation-dependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28092037/structural-characterization-of-monomeric-dimeric-state-of-p59-fyn-sh2-domain
#7
Radu Huculeci, Fabien Kieken, Abel Garcia-Pino, Lieven Buts, Nico van Nuland, Tom Lenaerts
Src homology 2 (SH2) domains are key modulators in various signaling pathways allowing the recognition of phosphotyrosine sites of different proteins. Despite the fact that SH2 domains acquire their biological functions in a monomeric state, a multitude of reports have shown their tendency to dimerize. Here, we provide a technical description on how to isolate and characterize by gel filtration, circular dichroism (CD), and nuclear magnetic resonance (NMR) each conformational state of p59(fyn) SH2 domain.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28077797/repression-of-fyn-related-kinase-in-breast-cancer-cells-is-associated-with-promoter-site-specific-cpg-methylation
#8
Edward T Bagu, Sayem Miah, Chenlu Dai, Travis Spriggs, Yetunde Ogunbolude, Erika Beaton, Michelle Sanders, Raghuveera K Goel, Keith Bonham, Kiven E Lukong
The triple-negative breast cancer subtype is highly aggressive and has no defined therapeutic target. Fyn-related kinase (FRK) is a non-receptor tyrosine kinase, reported to be downregulated in breast cancer and gliomas, where it is suggested to have tumor suppressor activity. We examined the expression profile of FRK in a panel of 40 breast cancer cells representing all the major subtypes, as well as in 4 non-malignant mammary epithelial cell lines. We found that FRK expression was significantly repressed in a proportion of basal B breast cancer cell lines...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28076826/identification-of-new-pyrrolo-2-3-d-pyrimidines-as-src-tyrosine-kinase-inhibitors-in%C3%A2-vitro-active-against-glioblastoma
#9
Francesca Musumeci, Anna Lucia Fallacara, Chiara Brullo, Giancarlo Grossi, Lorenzo Botta, Pierpaolo Calandro, Mario Chiariello, Miroslava Kissova, Emmanuele Crespan, Giovanni Maga, Silvia Schenone
In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src...
December 19, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28033507/regulatory-region-genetic-variation-is-associated-with-fyn-expression-in-alzheimer-s-disease
#10
Jeffrey A Zahratka, Yvonne Shao, McKenzie Shaw, Kaitlin Todd, Shane V Formica, Maria Khrestian, Thomas Montine, James B Leverenz, Lynn M Bekris
Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau, are a key pathologic feature of Alzheimer's disease (AD). Tau phosphorylation is under the control of multiple kinases and phosphatases, including Fyn. Previously, our group found an association between 2 regulatory single nucleotide polymorphisms in the FYN gene with increased tau levels in the cerebrospinal fluid. In this study, we hypothesized that Fyn expression in the brain is influenced by AD status and genetic content. We found that Fyn protein, but not messenger RNA, levels were increased in AD patients compared to cognitively normal controls and are associated with regulatory region single nucleotide polymorphisms...
March 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/27993968/mechanisms-of-acquired-drug-resistance-to-the-hdac6-selective-inhibitor-ricolinostat-reveals-rational-drug-drug-combination-with-ibrutinib
#11
Jennifer E Amengual, Sathyen A Prabhu, Maximilian Lombardo, Kelly M Zullo, Paul M Johannet, Yulissa Gonzalez, Luigi Scotto, Xavier Jirau-Serrano, Ying Wei, Jimmy K Duong, Renu Nandakumar, Serge Cremers, Akanksha Verma, Olivier Elemento, Owen A O'Connor
PURPOSE: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first in class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. EXPERIMENTAL DESIGN: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27975258/proximity-ligation-assay-a-tool-to-study-endogenous-interactions-between-tau-and-its-neuronal-partners
#12
Alexis Bretteville, Florie Demiautte, Julien Chapuis
Tau is a microtubule associated protein (MAP) that is expressed in neurons of the central nervous system. Tau proteins are deregulated in a group of pathologies, including Alzheimer's disease, commonly called tauopathies. Therefore intensive research has been conducted to understand both the regulation of Tau and its involvement in neuronal cellular pathways. Since its originally described interactor tubulin, Tau has been described to interact with several other proteins, including tyrosine kinases (Src, Fyn, Lck) and Phospholipase C-γ...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27940916/hierarchical-crmp2-posttranslational-modifications-control-nav1-7-function
#13
Erik T Dustrude, Aubin Moutal, Xiaofang Yang, Yuying Wang, May Khanna, Rajesh Khanna
Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27940153/fyn-kinase-regulates-translation-in-mammalian-mitochondria
#14
Emine C Koc, Jennifer L Miller-Lee, Hasan Koc
BACKGROUND: Mitochondrial translation machinery solely exists for the synthesis of 13 mitochondrially-encoded subunits of the oxidative phosphorylation (OXPHOS) complexes in mammals. Therefore, it plays a critical role in mitochondrial energy production. However, regulation of the mitochondrial translation machinery is still poorly understood. In comprehensive proteomics studies with normal and diseased tissues and cell lines, we and others have found the majority of mitochondrial ribosomal proteins (MRPs) to be phosphorylated...
March 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27926876/potentiation-of-synaptic-glun2b-nmdar-currents-by-fyn-kinase-is-gated-through-bdnf-mediated-disinhibition-in-spinal-pain-processing
#15
Michael E Hildebrand, Jian Xu, Annemarie Dedek, Yi Li, Ameet S Sengar, Simon Beggs, Paul J Lombroso, Michael W Salter
In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27926612/inhibitory-effect-of-a-redox-silent-analogue-of-tocotrienol-on-hypoxia-adaptation-in-prostate-cancer-cells
#16
Nobuya Shiozawa, Ryosuke Sugahara, Kozue Namiki, Chiaki Sato, Akira Ando, Ayami Sato, Nantiga Virgona, Tomohiro Yano
Prostate cancer (PCa) is one of the most common cancers in Western countries and acquires a malignant phenotype, androgen-independent growth. PCa under hypoxia often has resistance to chemotherapy and radiotherapy. However, an effective therapy against PCa under hypoxia has not yet been established. In this report, we investigated the inhibitory effect of a redox-silent analogue of tocotrienol on the survival of a human androgen-independent PCa cell line (PC3) under hypoxia. We found that the redox-silent analogue exerted a cytotoxic effect on PC3 cells in a dose-dependent manner irrespective of either hypoxia or normoxia...
March 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27913425/cd36-mediates-h2o2-induced-calcium-influx-in-lung-microvascular-endothelial-cells
#17
Karthik Suresh, Laura Servinsky, Jose Reyes, Clark Undem, Joel Zaldumbide, Otgonchimeg Rentsendorj, Sruti Modekurty, Jeffrey M Dodd-O, Alan Scott, David B Pearse, Larissa A Shimoda
Elevated levels of reactive oxygen species and intracellular Ca(2+) play a key role in endothelial barrier dysfunction in acute lung injury. We previously showed that H2O2-induced increases in intracellular calcium concentrations ([Ca(2+)]i) in lung microvascular endothelial cells (LMVECs) involve the membrane Ca(2+) channel, transient receptor potential vanilloid-4 (TRPV4) and that inhibiting this channel attenuated H2O2-induced barrier disruption in vitro. We also showed that phosphorylation of TRPV4 by the Src family kinase, Fyn, contributes to H2O2-induced Ca(2+) influx in LMVEC...
January 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27906494/alcohol-dependent-molecular-adaptations-of-the-nmda-receptor-system
#18
REVIEW
N Morisot, D Ron
Phenotypes such as motivation to consume alcohol, goal-directed alcohol seeking and habit formation take part in mechanisms underlying heavy alcohol use. Learning and memory processes greatly contribute to the establishment and maintenance of these behavioral phenotypes. The N-methyl-d-aspartate receptor (NMDAR) is a driving force of synaptic plasticity, a key cellular hallmark of learning and memory. Here, we describe data in rodents and humans linking signaling molecules that center around the NMDARs, and behaviors associated with the development and/or maintenance of alcohol use disorder (AUD)...
January 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/27898263/genetic-alterations-affecting-gtpases-and-t-cell-receptor-signaling-in-peripheral-t-cell-lymphomas
#19
Rebecca L Boddicker, Gina L Razidlo, Andrew L Feldman
Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy...
November 29, 2016: Small GTPases
https://www.readbyqxmd.com/read/27876060/20-year-follow-up-study-of-danish-hht-patients-survival-and-causes-of-death
#20
Anette Kjeldsen, Katrine Saldern Aagaard, Pernille Mathiesen Tørring, Sören Möller, Anders Green
BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is a dominantly inheritable disorder, with a wide variety of clinical manifestations due to presence of multiple arteriovenous manifestations. The most common mutations are found in HHT1 (ENG) and HHT2 (ACVRL1) patients, causing alterations in the TGF-β pathway which is responsible for angiogenesis. Modulations of angiogenesis may influence cancer rates. The objective of the study was to evaluate 20-year survival according to HHT subtype, as well as to evaluate differences in causes of death comparing HHT patients and controls...
November 22, 2016: Orphanet Journal of Rare Diseases
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