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The Receptor Tyrosine Kinase Trka Is Increased and Targetable in HER2-Positive Breast Cancer
biomolecules Article The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer Nathan Griffin 1,2, Mark Marsland 1,2, Severine Roselli 1,2, Christopher Oldmeadow 2,3, 2,4 2,4 1,2, , 1,2, John Attia , Marjorie M. Walker , Hubert Hondermarck * y and Sam Faulkner y 1 School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; nathan.griffi[email protected] (N.G.); [email protected] (M.M.); [email protected] (S.R.); [email protected] (S.F.) 2 Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, Australia; [email protected] (C.O.); [email protected] (J.A.); [email protected] (M.M.W.) 3 School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, NSW 2308, Australia 4 School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia * Correspondence: [email protected]; Tel.: +61-2492-18830; Fax: +61-2492-16903 Contributed equally to the study. y Received: 19 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 Abstract: The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). -
Expression of the Neurotrophic Tyrosine Kinase Receptors, Ntrk1 and Ntrk2a, Precedes Expression of Other Ntrk Genes in Embryonic Zebrafish
Expression of the neurotrophic tyrosine kinase receptors, ntrk1 and ntrk2a, precedes expression of other ntrk genes in embryonic zebrafish Katie Hahn, Paul Manuel and Cortney Bouldin Department of Biology, Appalachian State University, Boone, NC, USA ABSTRACT Background: The neurotrophic tyrosine kinase receptor (Ntrk) gene family plays a critical role in the survival of somatosensory neurons. Most vertebrates have three Ntrk genes each of which encode a Trk receptor: TrkA, TrkB, or TrkC. The function of the Trk receptors is modulated by the p75 neurotrophin receptors (NTRs). Five ntrk genes and one p75 NTR gene (ngfrb) have been discovered in zebrafish. To date, the expression of these genes in the initial stages of neuron specification have not been investigated. Purpose: The present work used whole mount in situ hybridization to analyze expression of the five ntrk genes and ngfrb in zebrafish at a timepoint when the first sensory neurons of the zebrafish body are being established (16.5 hpf). Because expression of multiple genes were not found at this time point, we also checked expression at 24 hpf to ensure the functionality of our six probes. Results: At 16.5 hpf, we found tissue specific expression of ntrk1 in cranial ganglia, and tissue specific expression of ntrk2a in cranial ganglia and in the spinal cord. Other genes analyzed at 16.5 hpf were either diffuse or not detected. At 24 hpf, we found expression of both ntrk1 and ntrk2a in the spinal cord as well as in multiple cranial ganglia, and we identified ngfrb expression in cranial ganglia at 24 hpf. -
Trkb Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders
Int. J. Mol. Sci. 2013, 14, 10122-10142; doi:10.3390/ijms140510122 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders Vivek K. Gupta 1,*, Yuyi You 1, Veer Bala Gupta 2, Alexander Klistorner 1,3 and Stuart L. Graham 1,3 1 Australian School of Advanced Medicine, Macquarie University, F10A, 2 Technology Place, North Ryde, Sydney, NSW 2109, Australia; E-Mails: [email protected] (Y.Y.); [email protected] (A.K.); [email protected] (S.L.G.) 2 Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia; E-Mail: [email protected] 3 Save Sight Institute, Sydney University, Sydney, NSW 2000, Australia * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +61-2-98-123-537; Fax: +61-2-98-123-600. Received: 27 March 2013; in revised form: 27 April 2013 / Accepted: 28 April 2013 / Published: 13 May 2013 Abstract: The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. -
Neurotrophins and Their Receptors: a Convergence Point for Many Signalling Pathways
REVIEWS NEUROTROPHINS AND THEIR RECEPTORS: A CONVERGENCE POINT FOR MANY SIGNALLING PATHWAYS Moses V.Chao The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through surprising interactions with other receptors and ion channels. 5,6 LONG-TERM POTENTIATION The era of growth factor research began fifty years ago receptor . Despite considerable progress in understand- (LTP).An enduring increase in with the discovery of nerve growth factor (NGF). Since ing the roles of these receptors, additional mechanisms the amplitude of excitatory then, the momentum to study the NGF — or neu- are needed to explain the many cellular and synaptic postsynaptic potentials as a rotrophin — family has never abated because of their interactions that occur between neurons. An emerging result of high-frequency (tetanic) stimulation of afferent continuous capacity to provide new insights into neural view is that neurotrophin receptors act as sensors for var- pathways. It is measured both as function; the influence of neurotrophins spans from ious extracellular and intracellular inputs, and several the amplitude of excitatory developmental neurobiology to neurodegenerative and new mechanisms have recently been put forward. Here, I postsynaptic potentials and as psychiatric disorders. In addition to their classic effects will consider several ways in which Trk and p75 receptors the magnitude of the postsynaptic-cell population on neuronal cell survival, neurotrophins can also regu- might account for the unique effects of neurotrophins spike. -
Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
cancers Review Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia Kalpana K. Bhanumathy 1,*, Amrutha Balagopal 1, Frederick S. Vizeacoumar 2 , Franco J. Vizeacoumar 1,3, Andrew Freywald 2 and Vincenzo Giambra 4,* 1 Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (A.B.); [email protected] (F.J.V.) 2 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (F.S.V.); [email protected] (A.F.) 3 Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada 4 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy * Correspondence: [email protected] (K.K.B.); [email protected] (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.) Simple Summary: Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase su- perfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies. -
Extracellular Juxtamembrane Motif Critical for Trkb Preformed Dimer and Activation
cells Article Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation Jianying Shen 1,2, Dang Sun 1, Jingyu Shao 1, Yanbo Chen 1, Keliang Pang 1, Wei Guo 1,3 and Bai Lu 1,3,* 1 School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China 2 Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100084, China 3 R & D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen 518057, China * Correspondence: [email protected]; Tel.: +86-10-6278-5101 Received: 29 May 2019; Accepted: 15 August 2019; Published: 19 August 2019 Abstract: Receptor tyrosine kinases are believed to be activated through ligand-induced dimerization. We now demonstrate that in cultured neurons, a substantial amount of endogenous TrkB, the receptor for brain-derived neurotrophic factor (BDNF), exists as an inactive preformed dimer, and the application of BDNF activates the pre-existing dimer. Deletion of the extracellular juxtamembrane motif (EJM) of TrkB increased the amount of preformed dimer, suggesting an inhibitory role of EJM on dimer formation. Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes. Finally, in cells co-expressing rat and human TrkB, MM12 could only activate TrkB human-human dimer but not TrkB human-rat TrkB dimer, indicating that MM12 binding to two TrkB monomers is required for activation. -
TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs
pharmaceuticals Review TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs Sun-Young Han Research Institute of Pharmaceutical Sciences and College of Pharmacy, Gyeongsang National University, Jinju-si 52828, Korea; [email protected] Abstract: Recently, two tropomycin receptor kinase (Trk) inhibitors, larotrectinib and entrectinib, have been approved for Trk fusion-positive cancer patients. Clinical trials for larotrectinib and entrectinib were performed with patients selected based on the presence of Trk fusion, regardless of cancer type. This unique approach, called tissue-agnostic development, expedited the process of Trk inhibitor development. In the present review, the development processes of larotrectinib and entrectinib have been described, along with discussion on other Trk inhibitors currently in clinical trials. The on-target effects of Trk inhibitors in Trk signaling exhibit adverse effects on the central nervous system, such as withdrawal pain, weight gain, and dizziness. A next generation sequencing-based method has been approved for companion diagnostics of larotrectinib, which can detect various types of Trk fusions in tumor samples. With the adoption of the tissue-agnostic approach, the development of Trk inhibitors has been accelerated. Keywords: Trk; NTRK; tissue-agnostic; larotrectinib; entrectinib; Trk fusion 1. Introduction Citation: Han, S.-Y. TRK Inhibitors: Tropomyosin receptor kinases (Trk) are tyrosine kinases encoded by neurotrophic Tissue-Agnostic Anti-Cancer Drugs. tyrosine/tropomyosin receptor kinase (NTRK) genes [1]. Chromosomal rearrangement of Pharmaceuticals 2021, 14, 632. https:// NTRK genes is found in cancer tissues [2]. The resulting fusion proteins containing part of doi.org/10.3390/ph14070632 the Trk protein have a constitutively active form of kinase that transduces deregulating signals. -
Brain-Derived Neurotrophic Factor Receptor Trkb Exists As a Preformed Dimer in Living Cells Jianying Shen1,2 and Ichiro N Maruyama1*
Shen and Maruyama Journal of Molecular Signaling 2012, 7:2 http://www.jmolecularsignaling.com/content/7/1/2 SHORTREPORT Open Access Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells Jianying Shen1,2 and Ichiro N Maruyama1* Abstract Background: Neurotrophins (NTs) and their receptors play crucial roles in the development, functions and maintenance of nervous systems. It is widely believed that NT-induced dimerization of the receptors initiates the transmembrane signaling. However, it is still controversial whether the receptor molecule has a monomeric or dimeric structure on the cell surface before its ligand binding. Findings: Using chemical cross-linking, bimolecular fluorescence complementation (BiFC) and luciferase fragment complementation (LFC) assays, in this study, we show the brain-derived neurotrophic factor (BDNF) receptor TrkB exists as a homodimer before ligand binding. We have also found by using BiFC and LFC that the dimer forms in the endoplasmic reticulum (ER), and that the receptor lacking its intracellular domain cannot form the dimeric structure. Conclusions: Most, if not all, of the TrkB receptor has a preformed, yet inactive, homodimeric structure before BDNF binding. The intracellular domain of TrkB plays a crucial role in the spontaneous dimerization of the newly synthesized receptors, which occurs in ER. These findings provide new insight into an understanding of a molecular mechanism underlying transmembrane signaling mediated by NT receptors. Keywords: BDNF, Chemical crosslinking, Protein fragment complementation assay, Neurotrophin receptor, Pre- formed homodimer Findings biologically unfavourable neuroblastomas, and TrkB The neurotrophin (NT) receptor family consists of the expression is associated with drug resistance and expres- tropomyosin-related kinase receptors (Trk) A, B and C, sion of angiogenic factors [5]. -
Trkc, a Receptor for Neurotrophin-3, Is Widely Expressed in the Developing Nervous System and in Non-Neuronal Tissues
Development 118, 463-475 (1993) 463 Printed in Great Britain © The Company of Biologists Limited 1993 trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues Lino Tessarollo, Pantelis Tsoulfas, Dionisio Martin-Zanca*, Debra J. Gilbert, Nancy A. Jenkins, Neal G. Copeland and Luis F. Parada† Molecular Embryology Section and Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201, USA *Present address: Instituto de Microbiologia Bioquimica CSIC, Departamento de Microbiologia, Facultad de Ciencias, 37008 Salamanca, Spain †Author for correspondence SUMMARY The Trk family of tyrosine kinases encodes receptors for insights into the role of Trk-family receptors and nerve nerve growth factor-related neurotrophins. Here we growth factor-related neurotrophins during develop- present a developmental expression study of trkC, which ment and suggest that, in addition to regulating neu- encodes a receptor for neurotrophin-3 (NT-3). Like the ronal survival and differentiation, the neurotrophin/Trk related genes, trk and trkB, trkC is expressed primarily receptor system may have broader physiological effects. in neural lineages although the pattern is complex and Finally, interspecific mouse backcrosses have been used includes non-neuronal cells. Direct comparison with trk to map the location of each of the Trk genes on mouse and trkB developmental expression patterns permits the chromosomes. Alignment with available chromosomal following observations. (1) trkC is expressed in novel maps identify possible linkage between the Trk genes neural tissues where other Trk genes are silent. (2) Some and known neurological mutations. tissues appear to coexpress trkB and trkC receptors in the embryo and in the adult. -
Trkb Deubiquitylation by USP8 Regulates Receptor Levels and BDNF
© 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs247841. doi:10.1242/jcs.247841 RESEARCH ARTICLE TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation Carlos Martın-Rodŕ ıgueź 1,2,*, Minseok Song3, Begoña Anta1,2, Francisco J. González-Calvo1, Rubén Deogracias1, Deqiang Jing4, Francis S. Lee4 and Juan Carlos Arevalo1,2,*,‡ ABSTRACT (RTK) family, initiate downstream signaling pathways in the Ubiquitylation of receptor tyrosine kinases (RTKs) regulates both the response to neurotrophin binding. Then, they are internalized and levels and functions of these receptors. The neurotrophin receptor localized to different subcellular compartments. Regulation of these TrkB (also known as NTRK2), a RTK, is ubiquitylated upon activation trafficking processes has been known to be coupled to Trk receptor by brain-derived neurotrophic factor (BDNF) binding. Although TrkB signaling specificity and duration. ubiquitylation has been demonstrated, there is a lack of knowledge Upon ligand binding, Trk receptors undergo various post- regarding the precise repertoire of proteins that regulates TrkB translational modifications (PTMs). Most notably, tyrosine ubiquitylation. Here, we provide mechanistic evidence indicating that phosphorylation generates binding sites for proteins that enable the ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF- recruitment of downstream signaling components (Arevalo and Wu, and TrkB-dependent neuronal differentiation. USP8 binds to the 2006). Another relevant PTM for Trk receptors is ubiquitylation, a C-terminus of TrkB using its microtubule-interacting domain (MIT). dynamic and reversible process in which ubiquitin is covalently Immunopurified USP8 deubiquitylates TrkB in vitro,whereas bound to the substrate by E3 ubiquitin ligases and can be knockdown of USP8 results in enhanced ubiquitylation of TrkB upon subsequently removed by deubiquitylases (DUBs). -
Rapid Nuclear Responses to Target-Derived Neurotrophins Require Retrograde Transport of Ligand–Receptor Complex
The Journal of Neuroscience, September 15, 1999, 19(18):7889–7900 Rapid Nuclear Responses to Target-Derived Neurotrophins Require Retrograde Transport of Ligand–Receptor Complex Fiona L. Watson,1,2,4 Heather M. Heerssen,1,2,4 Daniel B. Moheban,1,2,4 Michael Z. Lin,5 Claire M. Sauvageot,1,2,3 Anita Bhattacharyya,1,3,4 Scott L. Pomeroy,5 and Rosalind A. Segal1,2,4 1Program in Neuroscience, 2Department of Neurobiology, and 3Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, 4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and 5Division of Neuroscience, Department of Neurology, Children’s Hospital, Boston, Massachusetts 02115 Target-derived neurotrophins initiate signals that begin at nerve GFP) in live cells during retrograde signaling, we show that terminals and cross long distances to reach the cell bodies and TrkB-GFP moves rapidly from neurites to the cell bodies. This regulate gene expression. Neurotrophin receptors, Trks, them- rapid movement requires ligand binding, Trk kinase activity, and selves serve as retrograde signal carriers. However, it is not yet intact axonal microtubules. When they reach the cell bodies, known whether the retrograde propagation of Trk activation the activated TrkB receptors are in a complex with ligand. Thus, reflects movement of Trk receptors from neurites to cell bodies the retrograde propagation of activated TrkB from neurites to or reflects serial activation of stationary Trk molecules. Here, we cell bodies, although rapid, reflects microtubule-dependent show that neurotrophins selectively applied to distal neurites of transport of phosphorylated Trk–ligand complexes. Moreover, sensory neurons rapidly induce phosphorylation of the tran- the relocation of activated Trk receptors from nerve endings to scription factor cAMP response element-binding protein cell bodies is required for nuclear signaling responses. -
Novel Tumor-Specific Mutations in Receptor Tyrosine Kinase Subdomain IX Significantly Reduce Extracellular Signal-Regulated Kinase Activity
ANTICANCER RESEARCH 36: 2733-2744 (2016) Novel Tumor-specific Mutations in Receptor Tyrosine Kinase Subdomain IX Significantly Reduce Extracellular Signal-regulated Kinase Activity MASAKUNI SERIZAWA1, MASATOSHI KUSUHARA1,2, SUMIKO OHNAMI3, TAKESHI NAGASHIMA3,4, YUJI SHIMODA3,4, KEIICHI OHSHIMA5, TOHRU MOCHIZUKI5, KENICHI URAKAMI3 and KEN YAMAGUCHI6 1Drug Discovery and Development Division, 2Region Resources Division, 3Cancer Diagnostics Division, and 5Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan; 4SRL, Inc., Tokyo, Japan; 6Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan Abstract. Background/Aim: The identification of additional targeted cancer therapeutics against tumors with oncogenic therapeutic targets by clinical molecular profiling is necessary genetic alterations (4, 5). However, only a handful of patients to expand the range of molecular-targeted cancer with cancer actually benefit from effective molecular- therapeutics. This study aimed to identify novel functional targeted cancer therapeutics. In order to expand the range of tumor-specific single nucleotide variants (SNVs) in the kinase molecular-targeted cancer therapeutics, the identification of domain of receptor tyrosine kinases (RTKs), from whole-exome additional therapeutic targets through molecular profiling of sequencing (WES) data. Materials and Methods: SNVs were each patient with cancer is urgently needed (6). Therefore, selected from WES data of multiple cancer types using both the Shizuoka Cancer Center