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https://www.readbyqxmd.com/read/28335430/a-review-on-ubiquitination-of-neurotrophin-receptors-facts-and-perspectives
#1
REVIEW
Julia Sánchez-Sánchez, Juan Carlos Arévalo
Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75(NTR)) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination...
March 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28293395/expression-pattern-of-neurotrophins-and-their-receptors-during-neuronal-differentiation-of-adipose-derived-stem-cells-in-simulated-microgravity-condition
#2
Vajiheh Zarrinpour, Zahra Hajebrahimi, Mojtaba Jafarinia
OBJECTIVES: Studies have confirmed that microgravity, as a mechanical factor, influences both differentiation and function of mesenchymal stem cells. Here we investigated the effects of simulated microgravity on neural differentiation of human adipose-derived stem cells (ADSCs). MATERIALS AND METHODS: We have used a fast rotating clinostat (clinorotation) to simulate microgravity condition. Real-time PCR and flow cytometry analysis were used to evaluate the regulation of neurotrophins, their receptors, and neural markers by simulated microgravity and their impact on neural differentiation of cells...
February 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28279735/development-of-a-pharmacodynamic-biomarker-to-measure-target-engagement-from-inhibition-of-the-ngf-trka-pathway
#3
Eric A Price, Alicja Krasowska-Zoladek, Kausik K Nanda, Shawn J Stachel, Darrell A Henze
BACKGROUND: NGF signaling through TrkA triggers pathways involved in a wide range of biological effects. Clinical trials targeting either NGF or TrkA are ongoing to treat various diseases in the areas of oncology, neuroscience, and for pain, but there is no described measure of target engagement of TrkA in these studies. NEW METHOD: We have developed custom ELISA assays to measure NGF-induced phosphorylation of TrkA specific for rodent and human receptors. Optimized tissue processing methods allow for detection in both the brain and in skin...
March 7, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28266869/pig-induced-pluripotent-stem-cell-derived-neural-rosettes-parallel-human-differentiation-into-sensory-neural-subtypes
#4
Robin L Webb, Amalia Gallegos-Cárdenas, Colette N Miller, Nicholas J Solomotis, Hong-Xiang Liu, Franklin D West, Steven L Stice
The pig is the large animal model of choice for study of nerve regeneration and wound repair. Availability of porcine sensory neural cells would conceptually allow for analogous cell-based peripheral nerve regeneration in porcine injuries of similar severity and size to those found in humans. After recently reporting that porcine (or pig) induced pluripotent stem cells (piPSCs) differentiate into neural rosette (NR) structures similar to human NRs, here we demonstrate that pig NR cells could differentiate into neural crest cells and other peripheral nervous system-relevant cell types...
March 7, 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28215291/crystal-structures-of-neurotrophin-receptors-kinase-domain
#5
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/28174090/targeting-trk-family-proteins-in-cancer
#6
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/28159414/the-juxtamembrane-region-of-trka-kinase-is-critical-for-inhibitor-selectivity
#7
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
#8
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/28100780/a-novel-microrna-located-in-trkc-gene-regulates-wnt-signaling-pathway-and-is-differentially-expressed-in-colorectal-cancer-specimens
#9
Sadat Dokanehiifard, Atena Yasari, Hadi Najafi, Meisam Jafarzadeh, Maryam Nikkhah, Seyed Javad Mowla, Bahram M Soltani
Tropomyosin receptor kinase C (TrkC) is involved in cell survival, apoptosis, differentiation and tumorigenesis. TrkC diverse functions might be attributed to the hypothetical non-coding RNAs, embedded within the gene. Using bioinformatics approaches, a novel miRNA named TrkC-miR2 was predicted within TrkC gene, capable of regulating Wnt pathway. For experimental verification of this miRNA, predicted TrkC-premir2 sequence was overexpressed in SW480 cells, which led to the detection of two mature TrkC-miR2 isomiRs, and their endogenous forms were detected in human cell lines as well...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28039433/structural-characterization-of-nonactive-site-trka-selective-kinase-inhibitors
#10
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
https://www.readbyqxmd.com/read/28007784/an-ensemble-of-regulatory-elements-controls-runx3-spatiotemporal-expression-in-subsets-of-dorsal-root-ganglia-proprioceptive-neurons
#11
Elena Appel, Sarit Weissmann, Yehuda Salzberg, Kira Orlovsky, Varda Negreanu, Michael Tsoory, Calanit Raanan, Ester Feldmesser, Yael Bernstein, Orit Wolstein, Ditsa Levanon, Yoram Groner
The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3...
December 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/28002846/unchanged-neurotrophic-factors-and-their-receptors-correlate-with-sparing-in-extraocular-muscles-in-amyotrophic-lateral-sclerosis
#12
Vahid M Harandi, Aida R N Gaied, Thomas Brännström, Fatima Pedrosa Domellöf, Jing-Xia Liu
Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice. Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1)...
December 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27891557/exogenous-expression-of-nt-3-and-trkc-genes-in-bone-marrow-stromal-cells-elevated-the-survival-rate-of-the-cells-in-the-course-of-neural-differentiation
#13
Houri Edalat, Zahra Hajebrahimi, Vahid Pirhajati, Mahmoud Tavallaei, Mansoureh Movahedin, Seyed Javad Mowla
Bone marrow stromal cells (BMSCs) are attractive cellular sources for cell therapy of many diseases, specifically neurodegenerative ones. The potential capability of BMSCs could be further augmented by enhancing their neuroprotective property, differentiation potential, and survival rate subsequent to transplantation. Therefore, a concurrent upregulation of neurotrophin-3 (NT-3) and its high affinity receptor, tyrosin kinase C (TrkC), was utilized in our study. BMSCs were cotransfected with pDsRed1-N1-NT-3 and pCMX-TrkC plasmids before induction of neural differentiation...
November 28, 2016: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/27853305/tropomyosin-receptor-kinase-c-targeted-delivery-of-a-peptidomimetic-ligand-photosensitizer-conjugate-induces-antitumor-immune-responses-following-photodynamic-therapy
#14
Chin Siang Kue, Anyanee Kamkaew, Siew Hui Voon, Lik Voon Kiew, Lip Yong Chung, Kevin Burgess, Hong Boon Lee
Tropomyosin receptor kinase C (TrkC) targeted ligand-photosensitizer construct, IYIY-diiodo-boron-dipyrromethene (IYIY-I2-BODIPY) and its scrambled counterpart YIYI-I2-BODIPY have been prepared. IYIY-I2-BODIPY binds TrkC similar to neurotrophin-3 (NT-3), and NT-3 has been reported to modulate immune responses. Moreover, it could be shown that photodynamic therapy (PDT) elevates antitumor immune responses. This prompted us to investigate the immunological impacts mediated by IYIY-I2-BODIPY in pre- and post-PDT conditions...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27843590/ntrk-gene-fusions-as-novel-targets-of-cancer-therapy-across-multiple-tumour-types
#15
REVIEW
Alessio Amatu, Andrea Sartore-Bianchi, Salvatore Siena
The tropomyosin receptor kinase (Trk) receptor family comprises 3 transmembrane proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and play an essential role in the physiology of development and function of the nervous system through activation by neurotrophins. Gene fusions involving NTRK genes lead to transcription of chimeric Trk proteins with constitutively activated or overexpressed kinase function conferring oncogenic potential...
2016: ESMO Open
https://www.readbyqxmd.com/read/27830679/-effects-of-ischemia-on-the-expression-of-neurotrophins-and-their-receptors-in-rat-brain-structures-outside-the-lesion-site-including-on-the-opposite-hemisphere
#16
V G Dmitrieva, V V Stavchansky, O V Povarova, V I Skvortsova, S A Limborska, L V Dergunova
Neurotrophins stimulate the regeneration of neural tissue after lesions. It is also known that the sources of neurogenesis and cerebral function recovery are predominantly located in subcortical brain structures. The effects of ischemia on the expression of genes that encode neurotrophins (Bdnf, Ngf, Nt-3) and their receptors (TrkB, TrkA, TrkC, p75) in brain structures outside the lesion site were studied 3, 24, and 72 h after irreversible unilateral occlusion of the middle cerebral artery in rats. Changes in the mRNA expression of these genes were assessed by relative quantification using real-time RT-PCR...
September 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27775476/alteration-of-selected-neurotrophic-factors-and-their-receptor-expression-in-mouse-brain-response-to-whole-brain-irradiation
#17
Ewa Pius-Sadowska, Miłosz Piotr Kawa, Patrycja Kłos, Dorota Rogińska, Michał Rudnicki, Boehlke Marek, Piotr Waloszczyk, Bogusław Machaliński
Ionizing radiation can significantly affect brain function in children and young adults, particularly in the hippocampus where neurogenic niches are located. Injury to normal tissue is a major concern when whole-brain irradiation (WBI) is used to treat central nervous system (CNS) tumors, and the pathogenesis of this injury remains poorly understood. We assessed the expression of selected neurotrophins (NTs) and NT receptors (NTRs) in brains of young mice after a single 10 Gy gamma-ray exposure using morphological and molecular analyses [qRT-PCR, Western blot, immunohistochemistry (IHC)] to evaluate WBI-induced injury in its acute phase...
October 24, 2016: Radiation Research
https://www.readbyqxmd.com/read/27697534/emerging-roles-of-the-neurotrophin-receptor-trkc-in-synapse-organization
#18
Yusuke Naito, Alfred Kihoon Lee, Hideto Takahashi
Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPσ)...
September 30, 2016: Neuroscience Research
https://www.readbyqxmd.com/read/27695040/the-paradoxical-signals-of-two-trkc-receptor-isoforms-supports-a-rationale-for-novel-therapeutic-strategies-in-als
#19
Fouad Brahimi, Mario Maira, Pablo F Barcelona, Alba Galan, Tahar Aboulkassim, Katrina Teske, Mary-Louise Rogers, Lisa Bertram, Jing Wang, Masoud Yousefi, Robert Rush, Marc Fabian, Neil Cashman, H Uri Saragovi
Full length TrkC (TrkC-FL) is a receptor tyrosine kinase whose mRNA can be spliced to a truncated TrkC.T1 isoform lacking the kinase domain. Neurotrophin-3 (NT-3) activates TrkC-FL to maintain motor neuron health and function and TrkC.T1 to produce neurotoxic TNF-α; hence resulting in opposing pathways. In mouse and human ALS spinal cord, the reduction of miR-128 that destabilizes TrkC.T1 mRNA results in up-regulated TrkC.T1 and TNF-α in astrocytes. We exploited conformational differences to develop an agonistic mAb 2B7 that selectively activates TrkC-FL, to circumvent TrkC...
2016: PloS One
https://www.readbyqxmd.com/read/27688482/impact-of-aging-on-proprioceptive-sensory-neurons-and-intrafusal-muscle-fibers-in-mice
#20
Sydney K Vaughan, Olivia L Stanley, Gregorio Valdez
The impact of aging on proprioceptive sensory neurons and intrafusal muscle fibers (IMFs) remains largely unexplored despite the central function these cells play in modulating voluntary movements. Here, we show that proprioceptive sensory neurons undergo deleterious morphological changes in middle age (11- to 13-month-old) and old (15- to 21-month-old) mice. In the extensor digitorum longus and soleus muscles of middle age and old mice, there is a significant increase in the number of Ia afferents with large swellings that fail to properly wrap around IMFs compared with young adult (2- to 4-month-old) mice...
September 29, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
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