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FLASH GENE

Symbol

NTRK2

contributors: mct/shn - updated : 05-07-2016

HGNC name	neurotrophic tyrosine kinase, receptor, type 2
HGNC id	8032

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	EIEE58 epileptic encephalopathy, early infantile, 58
Location	9q21.33      Physical location : 87.283.465 - 87.638.505
Synonym name	GP145-TrkB
	tyrosine kinase receptor B
	tropomyosin-related kinase B
	trkB tyrosine kinase
	BDNF/NT-3 growth factors receptor
	BDNF-tropomyosine receptor kinase B
Synonym symbol(s)	TRKB, RP11-263K15.1, GP145-TrkB, trk-B
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	355.04 kb     24 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence
text structure	regulatory element designated TCaRE3 (TRKB Ca(2+) response element 3) required for CREB-dependen NTRK2 transcription in neurons (functional interaction between CREB1 bound to the CREs and KLF7 bound to TCaRE3 is essential for the proper regulation of NTRK2 in neurons.)

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D9S152 - D9S1877 - NTRK2 - D9S1790 - D9S1865 - qter

RNA

TRANSCRIPTS	type	messenger

text	a truncated non catalytic form (fetal brain)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001018065 17 splicing 8340 NP_001018075 61 553 only in the brain 2007 17889702 also called TrkB-T-Shc or variant d located in plasma membrane ,negative regulator of NTRK2 in the brain alternative exon 19 NM_001007097 13 - 7111 NP_001007098 53.1 477 - 2007 17889702 also called TrkB-T1 or variant b NM_001018064 20 - 5560 NP_001018074 92 822 - 2007 17889702 also called variant c NM_006180 21 - 5608 NP_006171 93.8 838 - 2007 17889702 also called variant a NM_001018066 16 - 8292 NP_001018076 59.2 537 - 2007 17889702 also called variant e

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain midbrain nuclei     Homo sapiens   brain hindbrain pons   predominantly Homo sapiens   brain midbrain substantia nigra   lowly Homo sapiens   brain hindbrain medulla oblongata   predominantly Homo sapiens Visual eye retina       Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Visual Muller cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal peptide,
	an extracellular domain consisting of three tandem leucine-rich motifs flanked by two cysteine clusters and two Ig-like domains
	a single transmembrane segment (1TM)
	an intracellular domain possessing a tyrosine-kinase domain

conjugated

mono polymer

dimer

HOMOLOGY

interspecies	ortholog to Ntrk2, Mus musculus
	ortholog to Ntrk2, rattus norvegicus
	ortholog to NTRK2, Pan troglodytes

Homologene

FAMILY

Trk family tyrosine kinases

CATEGORY

enzyme , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
text	receptor tyrosine kinase, class VI

basic FUNCTION	functional receptor for brain derived neurotrophic factor (BDNF)
	hippocampus-mediating learning
	essential to the development of GABAergic neurons and regulates synapse formation
	retinal BDNF/NTRK2 signaling has its primary role in the development of inner retinal neuronal circuits, and this action is not a secondary effect due to the loss of visual signaling in the outer retina
	modulate specific phases of fear learning and amygdalar synaptic plasticity through two main phosphorylation docking sites
	its activation stimulates the dendritic branching of mitral/tufted cells in developing olfactory bulb
	plays important roles in facilitating metastasis in various types of malignant tumors
	additional component that potentially might contribute to the altered neurotrophic support in Huntington disease
	with BDNF, are essential in promoting normal development of the central nervous system
	BDNF and NTRK2 play important roles in controlling respiration, movement, balance and feeding in the brainstem and that the NTRK2 is the most age-sensitive component of this system, especially in the hippocampus
	regulates the cell surface expression of KCNJ9
	unlike NTRK1 and NTRK3, does not trigger neuronal death
	potent suppressor of anoikis
	potential tag for synapse-specific expression of late-phase long-term potentiation and long-term memory
	BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults
	NTRK2 and PRKCZ, two critical regulators of synaptic plasticity, facilitate DLG4 targeting to synapses
	expression of NTRK2 and BDNF is associated with poor prognosis in non-small cell lung cancer patients
	is necessary for ciliary localization of NTRK2 receptor and activation by BDNF
	neurotrophin signaling via NTRK2 and NTRK3 promotes the growth of brain tumor-initiating cells
	plays a key role in tumorigenicity and metastasis of breast cancer cells through suppression of RUNX3 or KEAP1

CELLULAR PROCESS	cell life, differentiation
	cell organization/biogenesis

PHYSIOLOGICAL PROCESS

development , nervous system , neurogenesis

text	key regulator of cell fate and cell shape in CNS
	establishment of synapses (GABAergic in cerebellum)

PATHWAY

metabolism

signaling

signal transduction

	mediating BDNF signaling to sensory neurons
	BDNF/NTRK2 signaling activates PI3-kinase that promotes anterograde transport of NTRK2 in the putative axon, further enhancing local BDNF/NTRK2 signaling

a component

BDNF/NTRK2 signaling is essential for the development of photoreceptors and for synaptic communication between photoreceptors and second order retinal neurons

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	neurotrophin-3, NT-3
	brain-derived neurotrophic factor, BDNF
	Src family tyrosine kinase Fyn
	rAPS and SH2-B
	neurotrophin receptor p75(NTR)
	14 kDa light chain of cytoplasmic dynein
	neurotrophins NTF3 and NTF4
	Nck2
	ShcB and ShcC
	phospholipase Cgamma, PLCgamma
	p62
	ankyrin-rich transmembrane protein, ARMS
	Dok5
	neural cell adhesion molecule NCAM1 and KCNJ9
	RANBP9 may modulate NTRK2-mediated downstream signaling and biological functions
	PLCG1
	regulates BDNF-induced Erk activation and axonal filopodia formation
	LIMK1 (
	NTRK2 and NCAM1 are downstream targets of NEUROD1 that contribute to the actions of NEUROD1 in neuroendocrine lung
	key role for SORL1 in mediating BDNF trophic signaling by regulating the intracellular location of NTRK2
	HAP1 stabilized the association of NTRK2 with the intracellular sorting protein sortilin, prevented NTRK2 degradation, and promoted its anterograde transport
	BDNF, via truncated NTRK2, modulates SLC6A9 and SLC6A5 in astrocytes
	LINGO1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including NTRK1, NTRK2 and NTRK3
	NTRK2 plays a key role in regulation of the tumor suppressors RUNX3 and KEAP1
	LRIG1 physically interacts with NTRK2 and attenuates BDNF signaling
	MAPK8IP1, MAPK8IP3 cooperate to mediate NTRK2 anterograde axonal transport
	NDFIP1 mediates the ubiquitination of NTRK2, resulting in receptor trafficking predominantly on RAB7A containing late endosomes, highlighting a pathway for NTRK2 degradation at the lysosome

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

EIEE58

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --other   altered in Huntington disease tumoral     --over   in colon cancer possibly plays roles in inhibiting apoptosis, promoting proliferation and invasion, facilitating tumor progression by lymphangiogenesis-associated metastasis tumoral     --over   in disfiguring cutaneous appendageal tumours of CYLD tumoral fusion       NTRK2 is a new gene fusion target in pilocytic astrocytoma (fusion with QKI, FGFR1)

Susceptibility

to autism to Developmental and epileptic encephalopathy (DEE)

Variant & Polymorphism other	alterations in BDNF/NTRK2 signaling contribute to an increased vulnerability to autism
	p.Tyr434Cys variant is located at the beginning of the transmembrane domain of NTRK2 and has been identified in four individuals with DEE

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     NTRK2 blockade may be a new strategy for transitional cell carcinoma therapy neurology epilepsy   disruption of NTRK2-mediated PLCG1 signaling inhibits limbic epileptogenesis, and is a novel target for specific and effective therapeutic intervention neurology     manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases neurology     restoration of the physiological level of the TrkB.T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death, corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling in the trisomy 16 mouse model cancer brain glioma/neuroblstoma could be a target for combinatorial treatment of malignant glioma

ANIMAL & CELL MODELS

	knockout of trkB restricted to the mouse forebrain during postnatal development leads to increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms, impairment LTP at CA1 hippocampal synapses
	inhibitory interneurons are strongly affected, express reduced amounts of GABAergic markers and develop reduced numbers of GABAergic boutons and synaptic specializations in cerebellum of TrkB mutant mice
	mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets
	trkB(CaMKII-CRE) mice with a trkB-receptor disruption in the forebrain showed a stereotyped hyper-locomotion with reduced explorative activity, and impulsive reactions to novel stimuli
	in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity