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https://www.readbyqxmd.com/read/28218045/the-significance-of-trk-receptors-in-pancreatic-cancer
#1
Matthew D Johnson, Brandon Stone, Bryan J Thibodeau, Andrew M Baschnagel, Sandra Galoforo, Laura E Fortier, Billie Ketelsen, Samreen Ahmed, Zakiya Kelley, Alaa Hana, Thomas G Wilson, John M Robertson, Robert P Jury, George D Wilson
This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity...
February 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28215306/neurotrophin-receptors-and-perineural-invasion-analyses-in-select-lineage-unrelated-cutaneous-malignancies-with-a-propensity-for-perineural-invasion
#2
N F Frydenlund, M Mahalingam
In this chapter, we parse the literature on neurotrophins that have been implicated in the pathogenesis of perineural invasion (PNI) in select lineage-unrelated malignancies. We also detail evidence linking neurotrophins and their receptors (TrkA, RET, p75NGFR, and NCAM) to the pathogenesis of PNI in desmoplastic melanoma and cutaneous squamous cell carcinoma-both malignancies with an established propensity for PNI. Lastly, the clinical potential of neurotrophins as receptors for targeted therapies is explored...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28215292/emergent-role-of-coronin-1a-in-neuronal-signaling
#3
M Martorella, K Barford, B Winkler, C D Deppmann
The Coronin family of proteins were first noted for their role in pathogen-host interactions and for modulating actin dynamics. Recently, however, Coronins have been found in a greater variety of cell types, and novel roles for the Coronins within the nervous system have been discovered. In the immune system, Coronin-1a enables Mycobacterium tuberculosis to evade lysosomal destruction. This activity appears to be analogous to protection of the NGF-TrkA signaling endosome during sympathetic nervous system development that is required for survival signaling...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28215291/crystal-structures-of-neurotrophin-receptors-kinase-domain
#4
T Bertrand
Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28213521/signalling-adaptor-shcd-suppresses-erk-phosphorylation-distal-to-the-ret-and-trk-neurotrophic-receptors
#5
Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, Manali Tilak, Brianna Guild, Laura A New, Peihua Lu, Keévin Jacquet, Susan O Meakin, Nicolas Bisson, Nina Jones
Proteins of the 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...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28208669/the-role-of-nerve-growth-factor-ngf-and-its-precursor-forms-in-oral-wound-healing
#6
REVIEW
Karl Schenck, Olav Schreurs, Katsuhiko Hayashi, Kristen Helgeland
Nerve growth factor (NGF) and its different precursor forms are secreted into human saliva by salivary glands and are also produced by an array of cells in the tissues of the oral cavity. The major forms of NGF in human saliva are forms of pro-nerve growth factor (pro-NGF) and not mature NGF. The NGF receptors tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptor (p75(NTR)) are widely expressed on cells in the soft tissues of the human oral cavity, including keratinocytes, endothelial cells, fibroblasts and leukocytes, and in ductal and acinar cells of all types of salivary glands...
February 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28197073/association-of-trka-and-app-is-promoted-by-ngf-and-reduced-by-cell-death-promoting-agents
#7
Nadia Canu, Ilaria Pagano, Luca Rosario La Rosa, Marsha Pellegrino, Maria Teresa Ciotti, Delio Mercanti, Fabiola Moretti, Valentina Sposato, Viviana Triaca, Carla Petrella, Ichiro N Maruyama, Andrea Levi, Pietro Calissano
The amyloid precursor protein (APP) interacts with the tropomyosin receptor kinase A (TrkA) in normal rat, mouse, and human brain tissue but not in Alzheimer's disease (AD) brain tissue. However, it has not been reported whether the two proteins interact directly, and if so, which domains are involved. Clarifying these points will increase our understanding of the role and regulation of the TrkA/APP interaction in normal brain functioning as well as in AD. Here we addressed these questions using bimolecular fluorescence complementation (BiFC) and the proximity ligation assay (PLA)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28195068/expression-of-nerve-growth-factor-in-rat-stomach-implications-for-interactions-between-endothelial-neural-and-epithelial-cells
#8
A S Tarnawski, A Ahluwalia, M K Jones, T Brzozowski
: This study was aimed to determine the expression and localization of nerve growth factor (NGF) in the gastric mucosa. Transmural gastric specimens were obtained from euthanized rats. STUDIES: 1) expression of NGF and TrkA receptor by Western blotting; 2) histological evaluation of gastric wall architecture; 3) expression of NGF using immunostaining. Immunostaining showed strong and differential expression of NGF in neural elements of gastric myenteric and submucosal plexuses; in epithelial cells: mainly in chief and progenitor cells, in enterochromaffin-like (ECL) cells; and, in endothelial cells (ECs) lining blood vessels...
December 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28183697/safety-and-antitumor-activity-of-the-multi-targeted-pan-trk-ros1-and-alk-inhibitor-entrectinib-rxdx-101-combined-results-from-two-phase-1-trials-alka-372-001-and-startrk-1
#9
Alexander Drilon, Salvatore Siena, Sai-Hong Ignatius Ou, Manish Patel, Myung Ju Ahn, Jeeyun Lee, Todd M Bauer, Anna F Farago, Jennifer J Wheler, Stephen V Liu, Robert Doebele, Laura Giannetta, Giulio Cerea, Giovanna Marrapese, Michele Schirru, Alessio Amatu, Katia Bencardino, Laura Palmeri, Andrea Sartore-Bianchi, Angelo Vanzulli, Sara Cresta, Silvia Damian, Matteo Duca, Elena Ardini, Gang Li, Jason Christiansen, Karey Kowalski, Ann Johnson, Rupal Patel, David Luo, Edna Chow-Maneval, Zachary Hornby, Pratik S Multani, Alice T Shaw, Filippo G De Braud
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D...
February 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28174090/targeting-trk-family-proteins-in-cancer
#10
REVIEW
Yekaterina B Khotskaya, Vijaykumar R Holla, Anna F Farago, Kenna R Mills Shaw, Funda Meric-Bernstam, David S Hong
The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28161362/ngf-dependent-axon-growth-and-regeneration-are-altered-in-sympathetic-neurons-of-dystrophic-mdx-mice
#11
Loredana Lombardi, Irene Persiconi, Alessandra Gallo, Casper C Hoogenraad, Maria Egle De Stefano
Duchenne muscular dystrophy (DMD) is a lethal disease, determined by lack of dystrophin (Dp427), a muscular cytoskeletal protein also expressed by selected neuronal populations. Consequently, besides muscular wasting, both human patients and DMD animal models suffer several neural disorders. In previous studies on the superior cervical ganglion (SCG) of wild type and dystrophic mdx mice (Lombardi et al. 2008), we hypothesized that Dp427 could play some role in NGF-dependent axonal growth, both during development and adulthood...
February 2, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28160859/lindersin-b-from-lindernia-crustacea-induces-neuritogenesis-by-activation-of-tyrosine-kinase-a-phosphatidylinositol-3-kinase-extracellular-signal-regulated-kinase-signaling-pathway
#12
Lihong Cheng, Ying Ye, Lan Xiang, Hiroyuki Osada, Jianhua Qi
BACKGROUND: Neurotrophic factors such as nerve growth factor (NGF) play important roles in nervous system. NGF is a potential therapeutic drug for treatment of neurodegenerative diseases. However, because of physicochemical property, NGF cannot pass through the blood-brain barrier (BBB). Hence, small molecules which exhibit NGF-mimic activity and can pass through the BBB are considered to be promising drug candidates for treatment of such diseases. PURPOSE: The present study was designed to isolate NGF-mimic substance from extract of natural products, determine their structures and investigate mechanism of action of the active substance...
January 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28159414/the-juxtamembrane-region-of-trka-kinase-is-critical-for-inhibitor-selectivity
#13
Noritaka Furuya, Takaki Momose, Kenji Katsuno, Nobuhiko Fushimi, Hideyuki Muranaka, Chiaki Handa, Tomonaga Ozawa, Takayoshi Kinoshita
Although numerous crystal structures for protein kinases have been reported, many include only the kinase domain but not the juxtamembrane (JM) region, a critical activity-controlling segment of receptor tyrosine kinases (RTKs). In this study, we determined the X-ray crystal structure of the tropomyosin receptor kinase (Trk) A selective inhibitor A1 complexed with the TrkA kinase domain and the JM region. This structure revealed that the unique inhibitor-binding pocket created by a novel JM configuration yields significant potency and high selectivity against TrkB and TrkC...
January 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28133521/activation-of-neurotrophins-in-lumbar-dorsal-root-probably-contributes-to-neuropathic-pain-after-spinal-nerve-ligation
#14
Abdolreza Kazemi, Masoud Rahmati, Rasoul Eslami, Vahid Sheibani
OBJECTIVES: Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root. MATERIALS AND METHODS: Ten male Wistar rats were randomly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5)...
January 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28130123/small-molecule-antidepressant-amitriptyline-protects-hypoxia-reoxygenation-induced-cardiomyocyte-apoptosis-through-trka-signaling-pathway
#15
Yuxiang Dai, Shen Wang, Chenguang Li, Shufu Chang, Hao Lu, Zheyong Huang, Feng Zhang, Hongbo Yang, Yi Shen, Zhangwei Chen, Juying Qian, Junbo Ge
Hypoxia/reoxygenation (H/R) induced cardiomyocytes apoptosis is a major factor leading to cardiovascular diseases. In this study, we investigated the protective effect of small molecule antidepressant amitriptyline (AMP) in regulating H/R-induced apoptosis in neonatal mouse cardiomyocyte in culture. Cardiomyocytes of C57BL/6J mice were treated with H/R condition in vitro. Various concentration of AMP was added into culture 2h prior to H/R conditioning. Cardiomyocyte apoptosis was evaluated by TUNEL assay. AMP induced downstream signaling pathway proteins, including tropomyosin receptor kinase A receptor (TrkA), phosphor-TrkA (p-TrkA), protein kinase B (Akt) and phosphor-Akt (p-Akt) were probed by western blot...
January 24, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28128323/an-oxidoreductase-aioe-is-responsible-for-bacterial-arsenite-oxidation-and-resistance
#16
Qian Wang, Yushan Han, Kaixiang Shi, Xia Fan, Lu Wang, Mingshun Li, Gejiao Wang
Previously, we found that arsenite (As(III)) oxidation could improve the generation of ATP/NADH to support the growth of Agrobacterium tumefaciens GW4. In this study, we found that aioE is induced by As(III) and located in the arsenic island near the As(III) oxidase genes aioBA and co-transcripted with the arsenic resistant genes arsR1-arsC1-arsC2-acr3-1. AioE belongs to TrkA family corresponding the electron transport function with the generation of NADH and H(+). An aioE in-frame deletion strain showed a null As(III) oxidation and a reduced As(III) resistance, while a cytC mutant only reduced As(III) oxidation efficiency...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28122008/compromised-neurotrophic-and-angiogenic-regenerative-capability-during-tendon-healing-in-a-rat-model-of-type-ii-diabetes
#17
Aisha S Ahmed, Jian Li, Alim M D Abdul, Mahmood Ahmed, Claes-Göran Östenson, Paul T Salo, Carolyn Hewitt, David A Hart, Paul W Ackermann
Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats...
2017: PloS One
https://www.readbyqxmd.com/read/28069924/soluble-cpg15-from-astrocytes-ameliorates-neurite-outgrowth-recovery-of-hippocampal-neurons-after-mouse-cerebral-ischemia
#18
Jing-Jing Zhao, Jie-Xian Hu, De-Xin Lu, Chun-Xia Ji, Yao Qi, Xiao-Yan Liu, Feng-Yan Sun, Fang Huang, Ping Xu, Xian-Hua Chen
The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody...
February 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28067793/time-dependent-nerve-growth-factor-signaling-changes-in-the-rat-retina-during-optic-nerve-crush-induced-degeneration-of-retinal-ganglion-cells
#19
Louise A Mesentier-Louro, Sara De Nicolò, Pamela Rosso, Luigi A De Vitis, Valerio Castoldi, Letizia Leocani, Rosalia Mendez-Otero, Marcelo F Santiago, Paola Tirassa, Paolo Rama, Alessandro Lambiase
Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss...
January 5, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28039433/structural-characterization-of-nonactive-site-trka-selective-kinase-inhibitors
#20
Hua-Poo Su, Keith Rickert, Christine Burlein, Kartik Narayan, Marina Bukhtiyarova, Danielle M Hurzy, Craig A Stump, Xufang Zhang, John Reid, Alicja Krasowska-Zoladek, Srivanya Tummala, Jennifer M Shipman, Maria Kornienko, Peter A Lemaire, Daniel Krosky, Amanda Heller, Abdelghani Achab, Chad Chamberlin, Peter Saradjian, Berengere Sauvagnat, Xianshu Yang, Michael R Ziebell, Elliott Nickbarg, John M Sanders, Mark T Bilodeau, Steven S Carroll, Kevin J Lumb, Stephen M Soisson, Darrell A Henze, Andrew J Cooke
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
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