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Ret signaling

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https://www.readbyqxmd.com/read/28442998/glial-cell-line-derived-neurotrophic-factor-gene-delivery-in-parkinson-s-disease-a-delicate-balance-between-neuroprotection-trophic-effects-and-unwanted-compensatory-mechanisms
#1
REVIEW
Liliane Tenenbaum, Marie Humbert-Claude
Glial cell line-derived neurotrophic factor (GDNF) and Neurturin (NRTN) bind to a receptor complex consisting of a member of the GDNF family receptor (GFR)-α and the Ret tyrosine kinase. Both factors were shown to protect nigro-striatal dopaminergic neurons and reduce motor symptoms when applied terminally in toxin-induced Parkinson's disease (PD) models. However, clinical trials based on intraputaminal GDNF protein administration or recombinant adeno-associated virus (rAAV)-mediated NRTN gene delivery have been disappointing...
2017: Frontiers in Neuroanatomy
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#2
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28404375/synthesis-and-structure-activity-relationship-study-of-pyrazolo-3-4-d-pyrimidines-as-tyrosine-kinase-ret-inhibitors
#3
Chengyan Wang, Hongchun Liu, Zilan Song, Yinchun Ji, Li Xing, Xia Peng, Xisheng Wang, Jing Ai, Meiyu Geng, Ao Zhang
Three series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and evaluated as RET kinase inhibitors. Compounds 23a and 23c were identified to show significant activity both in the biochemical and the BaF3/CCDC6-RET cell assays. Compound 23c was found to significantly inhibit RET phosphorylation and down-stream signaling in BaF3/CCDC6-RET cells, confirming its potent cellular RET-targeting profile. Different from other RET inhibitors with equal potency against KDR that associated with severe toxicity, 23c did not show significant KDR-inhibition even at the concentration of 1μM...
March 31, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28382399/ccr5-in-recruitment-and-activation-of-myeloid-derived-suppressor-cells-in-melanoma
#4
REVIEW
Viktor Umansky, Carolin Blattner, Christoffer Gebhardt, Jochen Utikal
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment...
April 5, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28347966/a-novel-aptasensor-for-lysozyme-based-on-electrogenerated-chemiluminescence-resonance-energy-transfer-between-luminol-and-silicon-quantum-dots
#5
Yong-Ping Dong, Jiao Wang, Ying Peng, Jun-Jie Zhu
In the present work, electrogenerated chemiluminescence (ECL) of luminol was investigated in neutral condition at a gold electrode in the presence of silicon quantum dots (SiQDs). The results revealed that SiQDs can not only greatly enhance luminol ECL, but also act as energy acceptor to construct a novel ECL resonance energy transfer (ECL-RET) system with luminol. As a result, strong anodic ECL signal was obtained in neutral condition at the bare gold electrode, which is suitable for biosensing application...
March 22, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/28294980/microrna-146b-a-novel-biomarker-and-therapeutic-target-for-human-papillary-thyroid-cancer
#6
REVIEW
Chen-Kai Chou, Rue-Tusan Liu, Hong-Yo Kang
Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial...
March 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28281264/resonance-energy-transfer-based-nucleic-acid-hybridization-assays-on-paper-based-platforms-using-emissive-nanoparticles-as-donors
#7
Samer Doughan, M Omair Noor, Yi Han, Ulrich J Krull
Quantum dots (QDs) and upconverting nanoparticles (UCNPs) are luminescent nanoparticles (NPs) commonly used in bioassays and biosensors as resonance energy transfer (RET) donors. The narrow and tunable emissions of both QDs and UCNPs make them versatile RET donors that can be paired with a wide range of acceptors. Ratiometric signal processing that compares donor and acceptor emission in RET-based transduction offers improved precision, as it accounts for fluctuations in the absolute photoluminescence (PL) intensities of the donor and acceptor that can result from experimental and instrumental variations...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28213521/signaling-adaptor-shcd-suppresses-extracellular-signal-regulated-kinase-erk-phosphorylation-distal-to-the-ret-and-trk-neurotrophic-receptors
#8
Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, Manali Tilak, Brianna D Guild, Laura A New, Peihua Lu, Kévin Jacquet, Susan O Meakin, Nicolas Bisson, Nina Jones
Proteins of the Src homology and collagen (Shc) family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine-binding (PTB) domain...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28187790/retinoic-acid-and-tgf-%C3%AE-signalling-cooperate-to-overcome-mycn-induced-retinoid-resistance
#9
David J Duffy, Aleksandar Krstic, Melinda Halasz, Thomas Schwarzl, Anja Konietzny, Kristiina Iljin, Desmond G Higgins, Walter Kolch
BACKGROUND: Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance...
February 10, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28162975/comprehensive-molecular-characterization-of-pheochromocytoma-and-paraganglioma
#10
Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A Gordon Robertson, Amy R Johnson, Tara M Lichtenberg, Bradley A Murray, Hans K Ghayee, Tobias Else, Shiyun Ling, Stuart R Jefferys, Aguirre A de Cubas, Brandon Wenz, Esther Korpershoek, Antonio L Amelio, Liza Makowski, W Kimryn Rathmell, Anne-Paule Gimenez-Roqueplo, Thomas J Giordano, Sylvia L Asa, Arthur S Tischler, Karel Pacak, Katherine L Nathanson, Matthew D Wilkerson
We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28122586/mir-182-promotes-cancer-invasion-by-linking-ret-oncogene-activated-nf-%C3%AE%C2%BAb-to-loss-of-the-hes1-notch1-regulatory-circuit
#11
Alf Spitschak, Claudia Meier, Bhavani Kowtharapu, David Engelmann, Brigitte M Pützer
BACKGROUND: Dominant-activating mutations in the RET proto-oncogene, a receptor tyrosine kinase, are responsible for the development of medullary thyroid carcinoma (MTC) and causative for multiple endocrine neoplasia (MEN) type 2A and 2B. These tumors are highly aggressive with a high propensity for early metastasis and chemoresistance. This attribute makes this neoplasia an excellent model for probing mechanisms underlying cancer progression. METHODS: The expression level of miR-182 was measured in MTC tumor specimens and in TT cells by real-time RT-PCR...
January 26, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28018176/activated-microglia-induce-bone-marrow-mesenchymal-stem-cells-to-produce-glial-cell-derived-neurotrophic-factor-and-protect-neurons-against-oxygen-glucose-deprivation-injury
#12
Bingke Lv, Feng Li, Jie Fang, Limin Xu, Chengmei Sun, Jianbang Han, Tian Hua, Zhongfei Zhang, Zhiming Feng, Qinghua Wang, Xiaodan Jiang
In this study, we investigated interactions among microglia (MG), bone marrow mesenchymal stem cells (BMSCs) and neurons in cerebral ischemia and the potential mechanisms using an in vitro oxygen-glucose deprivation (OGD) model. Rat BMSCs were incubated with conditioned medium (CM) from in vitro cultures of OGD-activated rat MG and murine BV2 MG cells. Effects of glial cell-derived neurotrophic factor (GDNF) on rat neuron viability, apoptosis, lactate dehydrogenase (LDH) leakage and mitochondrial membrane potential (MMP) were analyzed in this model...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28013235/kinase-impact-assessment-in-the-landscape-of-fusion-genes-that-retain-kinase-domains-a-pan-cancer-study
#13
Pora Kim, Peilin Jia, Zhongming Zhao
Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies. Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet. To this end, we analyzed kinase domain retention (KDR) status in chimeric protein sequences of 914 KFGs covering 312 kinases across 13 major cancer types. Based on 171 kinase domain-retained KFGs including 101 kinases, we studied their recurrence, kinase groups, fusion partners, exon-based expression depth, short DNA motifs around the break points and networks...
December 24, 2016: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28011461/antitumor-activity-of-rxdx-105-in-multiple-cancer-types-with-ret-rearrangements-or-mutations
#14
Gang G Li, Romel Somwar, James Joseph, Roger S Smith, Takuo Hayashi, Leenus Martin, Aleksandra Franovic, Anni Schairer, Eric Martin, Gregory J Riely, Jason Harris, Shunqi Yan, Ge Wei, Jennifer W Oliver, Rupal Patel, Pratik Multani, Marc Ladanyi, Alexander Drilon
Purpose: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations...
December 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28009299/ret-functions-as-a-dual-specificity-kinase-that-requires-allosteric-inputs-from-juxtamembrane-elements
#15
Iván Plaza-Menacho, Karin Barnouin, Rachael Barry, Annabel Borg, Mariam Orme, Rakhee Chauhan, Stephane Mouilleron, Rubén J Martínez-Torres, Pascal Meier, Neil Q McDonald
Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/27994058/signal-transducer-and-activator-of-transcription-1-plays-a-pivotal-role-in-ret-ptc3-oncogene-induced-expression-of-indoleamine-2-3-dioxygenase-1
#16
Sonia Moretti, Elisa Menicali, Nicole Nucci, Pasquale Voce, Renato Colella, Rosa Marina Melillo, Federica Liotti, Silvia Morelli, Francesca Fallarino, Antonio Macchiarulo, Massimo Santoro, Nicola Avenia, Efisio Puxeddu
Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an immunosuppressive function as part of an acquired mechanism of immune escape. Recently, we demonstrated that IDO1 expression is significantly higher in all thyroid cancer histotypes compared with normal thyroid and that its expression levels correlate with T regulatory (Treg) lymphocyte densities in the tumor microenvironment. BRAF(V600E)- and RET/PTC3-expressing PcCL3 cells were used as cellular models for the evaluation of IDO1 expression in thyroid carcinoma cells and for the study of involved signal transduction pathways...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27988109/receptor-tyrosine-kinases-translocation-partners-in-hematopoietic-disorders
#17
REVIEW
Katelyn N Nelson, Malalage N Peiris, April N Meyer, Asma Siari, Daniel J Donoghue
Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation...
January 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27957853/characterization-of-the-direct-interaction-between-hybrid-sensor-kinases-pa1611-and-rets-that-controls-biofilm-formation-and-the-type-iii-secretion-system-in-pseudomonas-aeruginosa
#18
Anjali Y Bhagirath, Sai P Pydi, Yanqi Li, Chen Lin, Weina Kong, Prashen Chelikani, Kangmin Duan
One of the leading causes of morbidity and mortality in cystic fibrosis (CF) patients is pulmonary infection with Pseudomonas aeruginosa, and the pathophysiology of pulmonary infection in CF is affected by the lifestyle of this micro-organism. RetS-GacS/A-RsmA is a key regulatory pathway in P. aeruginosa that determines the bacterium's lifestyle choice. Previously, we identified PA1611, a hybrid sensor kinase, as a new player in this pathway that interacts with RetS and influences biofilm formation and type III secretion system...
December 13, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27935748/atf4-targets-ret-for-degradation-and-is-a-candidate-tumor-suppressor-gene-in-medullary-thyroid-cancer
#19
Rozita Bagheri-Yarmand, Michelle D Williams, Elizabeth G Grubbs, Robert F Gagel
Context: Medullary thyroid cancer (MTC) is an aggressive tumor that harbors activating mutations of the RET proto-oncogene. We previously reported that RET inhibits transcriptional activity of ATF4, the master regulator of the stress response pathway, to prevent cell death. Objective: We hypothesized that loss of function of ATF4 plays a role in initiation of MTC. Design: Targeted deletion of Atf4 in mice was used to assess ATF4 function in the thyroid gland...
March 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27933682/highly-efficient-intramolecular-electrochemiluminescence-energy-transfer-for-ultrasensitive-bioanalysis-of-aflatoxin-m1
#20
Jia-Li Liu, Min Zhao, Ying Zhuo, Ya-Qin Chai, Ruo Yuan
The intermolecular electrochemiluminescence resonance energy transfer (ECL-RET) between luminol and Ru(bpy)3(2+) was studied extensively to achieve the sensitive bioanalysis owing to the perfect spectral overlap of the donor and acceptor, but it still suffers from the challenging issue of low energy-transfer efficiency. The intramolecular ECL-RET towards the novel ECL compound containing the donor of luminol and the acceptor of Ru(bpy)2 (mcpbpy)(2+) (Lum-Ru) was designed and investigated. With the high-efficient ECL-RET in one molecule, the highly intense ECL signal of Lum-Ru was obtained owing to the short path of energy transmission and less energy loss between luminol and Ru(bpy)2 (mcpbpy)(2+) ...
December 8, 2016: Chemistry: a European Journal
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